WO2000015609A1 - Derives d'azetidine, leur preparation et les medicaments les contenant - Google Patents

Derives d'azetidine, leur preparation et les medicaments les contenant Download PDF

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Publication number
WO2000015609A1
WO2000015609A1 PCT/FR1999/002147 FR9902147W WO0015609A1 WO 2000015609 A1 WO2000015609 A1 WO 2000015609A1 FR 9902147 W FR9902147 W FR 9902147W WO 0015609 A1 WO0015609 A1 WO 0015609A1
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Prior art keywords
methyl
methylsulfonyl
chlorophenyl
azetidine
methylene
Prior art date
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PCT/FR1999/002147
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English (en)
French (fr)
Inventor
Daniel Achard
Hervé Bouchard
Jean Bouquerel
Marc Capet
Serge Grisoni
Jean-Luc Malleron
Serge Mignani
Augustin Hittinger
Original Assignee
Aventis Pharma S.A.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
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Publication date
Priority to AT99941728T priority Critical patent/ATE239703T1/de
Application filed by Aventis Pharma S.A. filed Critical Aventis Pharma S.A.
Priority to PL346530A priority patent/PL198526B1/pl
Priority to AU55232/99A priority patent/AU772025B2/en
Priority to CA002342739A priority patent/CA2342739C/fr
Priority to IL14176999A priority patent/IL141769A0/xx
Priority to JP2000570149A priority patent/JP4767413B2/ja
Priority to EP99941728A priority patent/EP1112251B1/de
Priority to BR9913592-2A priority patent/BR9913592A/pt
Priority to DE69907698T priority patent/DE69907698T2/de
Priority to DK99941728T priority patent/DK1112251T3/da
Priority to HU0103341A priority patent/HUP0103341A3/hu
Publication of WO2000015609A1 publication Critical patent/WO2000015609A1/fr
Priority to IL141769A priority patent/IL141769A/en
Priority to NO20011216A priority patent/NO321480B1/no
Priority to US09/803,723 priority patent/US6518264B2/en
Priority to US10/320,344 priority patent/US6858603B2/en
Priority to US10/870,274 priority patent/US20040235816A1/en
Priority to AU2004203078A priority patent/AU2004203078B2/en
Priority to US11/420,238 priority patent/US20060270649A1/en

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Definitions

  • the present invention relates to azetidine derivatives of formula:
  • R represents a chain
  • R represents a methyl or ethyl radical
  • R. represents either an aromatic chosen from phenyl, naphthyl or indenyl, these aromatics being unsubstituted or substituted by one or more halogen, alkyl, alkoxy, -CO-alk, hydroxy, -COOR 5 , formyl, trifluoromethyl, trifluoromethylsulfanyl, trifluoromethoxy, nitro, -NR 6 R 7 , -CO-NH-NR 6 R 7 , -N (alk) COOR 8 , cyano, -CONHR ,, -CO-NR 16 R l7 , alkylsulfanyl, hydroxyalkyl, -O-alk -NR 12 R 13 or alkylthioalkyl is a heteroaromatic chosen from benzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl, chromannyl, 2,3-dihydrobenzofuryl,
  • R 3 and R 4 identical or different, represent either an aromatic chosen from phenyl, naphthyl or indenyl, these aromatics being unsubstituted or substituted by one or more halogen, alkyl, alkoxy, formyl, hydroxy, trifluoromethyl, trifluoromethoxy , -CO-alk, cyano, -COOR 5 , -CONR 10 R,tician-CO-NH-NR 6 R 7 , alkylsulfanyl, hydroxyalkyl, -alk-NR 6 R 7 or alkylthioalkyl; or a heteroaromatic chosen from the benzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl, chromannyl, 2,3-dihydrobenzofuryl, 2,3-dihydrobenzothienyl, furyl, isochromannyl, isoquinolyl, pyrrolyl, quinolyl, 1,2,3,4-t
  • R 5 is an alkyl or phenyl radical optionally substituted by one or more halogen atoms
  • R 6 and R 7 identical or different, represent a hydrogen atom or an alkyl, -COOalk, cycloalkyl, alkylcycloalkyl, -alk-O-alk, hydroxyalkyl radical or else R 6 and R 7 form together with the atom nitrogen to which they are attached a saturated or unsaturated mono or bicyclic heterocycle having 3 to 10 members, optionally containing another heteroatom chosen from oxygen, sulfur and nitrogen and being optionally substituted by one or more alkyl radicals, -COalk, -COOalk, -CO -NHalk, -CS-NHalk, -CO-alk-NR ] 4 R 15 , oxo, hydroxyalkyl, -alk-O-alk, -CO-NH-,
  • R represents an alkyl radical
  • R 9 represents a hydrogen atom or an alkyl or alkyl radical substituted by dialkylamino, phenyl, cycloalkyl (optionally substituted by -COOalk) or a mono or bicyclic saturated or unsaturated heterocycle having 3 to 10 members, optionally containing a or several heteroatoms chosen from oxygen, sulfur and nitrogen and being optionally substituted by one or more alkyl radicals,
  • R 10 and R n identical or different, represent a hydrogen atom or an alkyl radical or else R l0 and R u form together with the nitrogen atom to which they are attached a saturated mono or bicyclic heterocycle having 3 to 10 links, optionally containing another heteroatom chosen from oxygen, sulfur and nitrogen and being optionally substituted by an alkyl radical,
  • R 12 and R 13 which may be identical or different, represent a hydrogen atom or an alkyl or cycloalkyl radical, or else R 12 and R ⁇ together with the nitrogen atom to which they are attached form a saturated mono or bicyclic heterocycle having 3 with 10 links, optionally containing another heteroatom chosen from oxygen, sulfur and nitrogen and being optionally substituted by an alkyl radical, -COalk, -COOalk, -CO-NHalk, -CS-NHalk, -CO-alk-NR l4 R, 5 or a saturated mono or bicyclic heterocycle having 3 to 10 members and containing a heteroatom chosen from oxygen, sulfur and nitrogen,
  • R 14 and R 15 which may be identical or different, represent a hydrogen atom or an alkyl or -COOalk radical
  • R, 6 and R 17 together with the nitrogen atom to which they are attached form a saturated mono or bicyclic heterocycle having 3 to 10 links, optionally containing another heteroatom chosen from oxygen, sulfur and nitrogen,
  • R ' represents a hydrogen atom or a radical -CO-alk
  • alk represents an alkyl or alkylene radical.
  • the alkyl and alkylene radicals and portions and the alkoxy radicals and portions are in straight or branched chain and contain 1 to 6 carbon atoms.
  • alkyl radicals mention may be made of methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, pentyl, hexyl radicals.
  • alkoxy radicals mention may be made of the methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy, pentyloxy radicals.
  • halogen includes chlorine, fluorine, bromine and iodine.
  • R 2 and / or R 3 and / or R 4 independently represent a substituted phenyl, this is preferably mono, di or trisubstituted.
  • R 6 and R 7 form together with the nitrogen atom to which they are attached a mono or bicyclic heterocycle, saturated or unsaturated having 3 to 10 members this is preferably an azetidinyl, pyrrolidinyl, piperazinyl, piperidyl, morpholi ring - nyle, imidazolyle, thiomorpholinyle ou uryl, these cycles being optionally substituted by an alkyl, hydroxyalkyle, -alk-O-alk, -CONH 2 , -COalk, -COOalk, oxo, -CSNHalk, -CONHalk or -CO radical -alk-NR 14 R 15 and, in particular, by a methyl, ethyl, propyl, isobutyl, acetyl, N, N-dimethylamino-methylcarbonyl, methyloxycarbonyl, methylcarbamoyl, methylthiocarbamo
  • R 10 and R u form together with the nitrogen atom to which they are attached a mono or bicyclic heterocycle saturated and having 3 to 10 members, it is preferably an azetidinyl, pyrrolidinyl, piperazinyl, piperidyl, morpholinyl or thiomorpholinyl, these rings being optionally substituted by an alkyl.
  • R 12 and R 13 form together with the nitrogen atom to which they are attached a mono or bicyclic heterocycle saturated and having 3 to 10 members, it is preferably an azetidinyl, pyrrolidinyl, piperazinyl, piperidyl, morpholinyl or thiomorpholinyl, these rings being optionally substituted by an alkyl radical, -COalk, -COOalk, -CO-NHalk, -CS-NHalk, -CO-alk-NR 14 R, 5 or a saturated mono or bicyclic heterocycle having 3 to 10 members and containing a heteroatom chosen from oxygen, sulfur and nitrogen, and, in particular, by a thiomorpholinyl radical.
  • R 16 and R 17 form together with the nitrogen atom to which they are attached a mono or bicyclic heterocycle saturated and having 3 to 10 links, this is preferably a piperidyl ring.
  • R represents an alkyl radical substituted by a saturated or unsaturated mono or bicyclic heterocycle having 3 to 10 members, optionally containing one or more heteroatoms chosen from oxygen, sulfur and nitrogen, the latter is preferably a pyrrolidinyl, tetrahydrofuryl ring, morpholinyl, pyrrolyl, these rings being optionally substituted by one or more alkyl radicals.
  • the compounds of formula (I) can be in the form of enantiomers and diastereoisomers. These optical isomers and their mixtures are part of the invention.
  • RR ,, R 3 and R 4 have the same meanings as in formula (I) and R "represents a hydroxy, methanesulfonyloxy or acetyloxy radical.
  • R represents a hydroxy, methanesulfonyloxy or acetyloxy radical.
  • the derivatives are used for which R "is a methanesulfonyloxy or acetyloxy radical obtained from the corresponding derivative for which R" is a hydroxy radical by the action of methane sulfonyl chloride or acetyl chloride, within a inert solvent such as pyridine, tetrahydrofuran, dioxane, a chlorinated solvent (dichloromethane, chloroform for example), at a temperature between 5 ° C and 20 ° C and then treated with a base such as hydroxide alkali metal (sodium hydroxide for example), an alkali metal carbonate (sodium or potassium carbonate for example), an amine such as a trialkylamine (triethylamine for example), 4-dimethylaminopyridine, diaza-l, 8 -bicyclo [5.4.0] undecene-7, at a temperature between 0 ° C and the boiling temperature of the reaction medium.
  • an inert solvent such as an ether (tetrahydrofuran for example)
  • a strong base such as lithium diisopropylamide, potassium tert-butoxide or n-butyllithium, at a temperature between -70 ° C and -15 ° C.
  • Hal represents a halogen atom and, preferably, chlorine, bromine or iodine, R, and R 2 have the same meanings as in formula (I).
  • Reaction (a) is generally carried out in an inert solvent such as dimethylformamide or an aliphatic alcohol 1-4C, at a temperature between 20 and 30 ° C.
  • an inert solvent such as dimethylformamide or an aliphatic alcohol 1-4C
  • Reaction (b) is carried out by any known method making it possible to oxidize a sulfur derivative without affecting the rest of the molecule such as those described by M. HUDLICKY, Oxidations in Organic Chemistry, ACS Monograph, 186, 252-263 (1990) .
  • the operation is carried out by the action of an organic peroxyacid or a salt of such a peroxyacid (peroxycarboxylic or peroxysulfonic acids, in particular peroxybenzoic acid, 3-chloroperoxybenzoic acid, 4-nitroperoxybenzoic acid, peroxyacetic acid , trifluoroperoxyacetic acid, peroxyformic acid, monoperoxyphthalic acid) or mineral peracids or a salt of such an acid (for example periodic or persulfuric acid), within an inert solvent such as chlorinated solvent (chloroform, dichloromethane for example), at a temperature between 0 and 25 ° C.
  • an organic peroxyacid or a salt of such a peroxyacid peroxycarboxylic or peroxysulfonic acids, in particular peroxybenzoic acid, 3-chloroperoxybenzoic acid, 4-nitroperoxybenzoic acid, peroxyacetic acid , trifluoroperoxyacetic acid, peroxyformic acid,
  • Peroxide can also be used of hydrogen or a periodate (sodium periodate for example), in an inert solvent such as an aliphatic alcohol 1-4C (methanol, ethanol for example), water or a mixture of these solvents, at a temperature between 0 and 20 ° C. It is also possible to operate by means of tert-butyl hydroperoxide in the presence of titanium tetraisopropylate in an aliphatic alcohol 1-4C (methanol, ethanol for example) or a water-alcohol mixture, at a temperature in the region of 25 °.
  • an inert solvent such as an aliphatic alcohol 1-4C (methanol, ethanol for example), water or a mixture of these solvents
  • oxone R potassium peroxymonosulfate
  • an aliphatic alcohol 1-4C methanol, ethanol for example
  • water, acetic acid or sulfuric acid at a temperature close to 20 ° C.
  • Reaction (c) is preferably carried out in an inert solvent such as an aliphatic alcohol 1-4C (methanol, ethanol for example), at a temperature between 20 ° C and the boiling temperature of the medium reactive.
  • an inert solvent such as an aliphatic alcohol 1-4C (methanol, ethanol for example)
  • the derivatives of formula (IV) are marketed or can be obtained by application or adaptation of the methods described in the examples.
  • the methyl derivative or the corresponding alcohol is halogenated, by means of a halogenating agent such as hydrobromic acid, within acetic acid, at a temperature in the region of 20 ° C. or the N-bromo or N-chlorosuccinimide in the presence of benzoyl peroxide, in an inert solvent such as tetrachloromethane, at the boiling temperature of the reaction medium.
  • a halogenating agent such as hydrobromic acid
  • acetic acid a temperature in the region of 20 ° C.
  • an inert solvent such as tetrachloromethane
  • azetidinones of formula (III) can be obtained by application or adaptation of the methods described by KATRITZKY AR et al., J. Heterocycl. Chem., 271 (1994), or DAVE PR, J. Org. Chem., 61, 5453 (1996) and in the examples.
  • KATRITZKY AR et al. J. Heterocycl. Chem., 271 (1994)
  • DAVE PR J. Org. Chem., 61, 5453 (1996) and in the examples.
  • R 3 and R 4 have the same meanings as in formula (I) and X represents a chlorine or bromine atom.
  • step A the operation is preferably carried out in an inert solvent such as an aliphatic alcohol 1-4C (ethanol, methanol for example), optionally in the presence of an alkali metal hydroxide, at the temperature of boiling of the reaction medium.
  • an inert solvent such as an aliphatic alcohol 1-4C (ethanol, methanol for example)
  • an alkali metal hydroxide optionally in the presence of an alkali metal hydroxide
  • step B the reduction is generally carried out, using lithium aluminum hydride, within tetrahydrofuran at the boiling temperature of the reaction medium.
  • step C the operation is preferably carried out in an inert solvent such as an aliphatic alcohol 1-4C (ethanol, methanol for example), in the presence of sodium hydrogen carbonate, at a temperature of between 20 ° C. and the boiling point of the reaction medium.
  • stage D it is preferably oxidized within DMSO, by means of the sulfur trioxide-pyridine complex, at a temperature in the region of 20 ° C. or by means of dimethylsulfoxide, in the presence of oxalyl chloride and triethylamine. , at a temperature between -70 and -50 ° C.
  • step E the operation is carried out according to the method described by GRISAR M. et al. in J. Med. Chem., 885 (1973).
  • the magnesium of the bromine derivative is formed and then the nitrile is reacted, in an ether such as ethyl ether, at a temperature between 0 ° C and the boiling temperature of the reaction medium.
  • an ether such as ethyl ether
  • the intermediate imine is reduced in situ with sodium borohydride at a temperature between 0 ° C and the boiling temperature of the reaction medium.
  • the R 3 -CO-R 4 derivatives are marketed or can be obtained by application or adaptation of the methods described by KUNDER NG et al. J. Chem. Soc. Perkin Trans 1, 2815 (1997); MORENO-MARRAS M., Eur. J. Med. Chem., 23 (5) 477 (1988); SKINNER et al., J. Med. Chem., J (6) 546 (1971); HURN NK, Tet. Lett., 36 (52) 9453 (1995); MEDICI A. et al., Tet. Lett., 24 (28) 2901 (1983); RIECKE RD et al., J. Org. Chem., 62 (20) 6921 (1997); KNABE J.
  • R 3 Br derivatives are marketed or can be obtained by application or adaptation of the methods described by BRANDSMA L. et al., Synth. Comm., 20 (11) 1697 and 3153 (1990); LEMAIRE M. et al., Synth. Comm., 24 (1) 95 (1994); GODA H. et al., Synthesis, 9,849 (1992); BAEUERLE P. et al., J. Chem. Soc. Perkin Trans 2, 489 (1993).
  • R 4 CN derivatives are marketed or can be obtained by application or adaptation of the methods described by BOUYSSOU P. et al., J. Het. Chem., 29 (4) 895 (1992); SUZUKI N. et al., J. Chem. Soc. Chem. Comm., 1523 (1984); MARBURG S. et al., J. Het. Chem., 12 1333 (1980); PERCEC V. et al., J. Org. Chem., 60 (21) 6895 (1995).
  • This reaction is generally carried out in the presence of a base such as an alkali metal carbonate (potassium carbonate for example), in an inert solvent such as acetonitrile, at the boiling point of the reaction medium.
  • a base such as an alkali metal carbonate (potassium carbonate for example)
  • an inert solvent such as acetonitrile
  • the derivatives of formula (VII) can be obtained by hydrolysis of a derivative of formula:
  • R, and R 2 have the same meanings as in formula (I).
  • This reaction is generally carried out by means of hydrochloric acid, in an inert solvent such as an ether (dioxane for example), at a temperature in the region of 20 ° C.
  • an inert solvent such as an ether (dioxane for example)
  • the derivatives of formula (VIII) are obtained by the action of vinyl chloroformate on a compound of formula (I) corresponding to R represents a chain of formula (B), R 'represents a hydroxy radical, R 3 and R 4 are radicals phenyl, in an inert solvent such as a chlorinated solvent (dichloromethane, chloroform for example), at a temperature between 0 ° C and the boiling temperature of the reaction mixture.
  • a chlorinated solvent dichloromethane, chloroform for example
  • the compounds of formula (I) for which R is a chain (B) in which R 'is a radical -CO-alk can be prepared by the action of a halide Hal-CO-alk in which Hal represents a halogen atom and preferably a chlorine atom and alk represents an alkyl radical on a corresponding compound of formula (I) for which R is a chain (B) in which R 'is a hydrogen atom.
  • This reaction is generally carried out in an inert solvent such as tetrahydrofuran, dioxane, a chlorinated solvent (dichloromethane, chloroform for example), at a temperature between -50 ° C and 20 ° C, in the presence of n -butyllithium.
  • an inert solvent such as tetrahydrofuran, dioxane, a chlorinated solvent (dichloromethane, chloroform for example
  • the compounds of formula (I) for which R 2 represents an aromatic or a heteroaromatic substituted by -NR 6 R 7 in which R 6 and R 7 each represent a hydrogen atom can also be prepared by reduction of a compound of formula (I) correspondent for which R 2 represents an aromatic or a heteroaromatic substituted by nitro.
  • This reaction is carried out by any known method which makes it possible to reduce a nitro to amino without affecting the rest of the molecule.
  • iron is used in the presence of hydrochloric acid in a 1-4C aliphatic alcohol such as ethanol, at the boiling temperature of the reaction medium.
  • the compounds of formula (I) for which R 2 represents an aromatic or heteroaromatic substituted by -CONHR, and / or R 3 and / or R 4 represent an aromatic or heteroaromatic substituted by -CONR l0 R ⁇ can also be prepared by action of a corresponding compound of formula (I) for which R 2 and / or R 3 and / or R 4 represent an aromatic or a heteroaromatic substituted by -COOR 5 for which R 5 is alkyl or phenyl optionally substituted by halogens, with respectively an amine H.NR, or HNR 10 R n for which R ,, R 10 and R M have the same meanings as in formula (I).
  • This reaction is generally carried out in an inert solvent such as a chlorinated solvent (dichloromethane, chloroform for example) or an aliphatic alcohol 1-4C (methanol, ethanol for example), at a temperature between 0 ° C and the boiling temperature of the reaction mixture.
  • a chlorinated solvent dichloromethane, chloroform for example
  • an aliphatic alcohol 1-4C methanol, ethanol for example
  • the compounds of formula (I) for which R 1 represents an aromatic substituted by hydroxy and / or R 3 and / or R 4 represent an aromatic or a heteroaromatic substituted by hydroxy can also be prepared by hydrolysis of a compound of formula (I ) corresponding for which R 2 represents an aromatic substituted by alkoxy and / or R 3 and / or R 4 represents an aromatic or a heteroaromatic substituted by alkoxy.
  • This reaction is carried out by any method of hydrolysis of an alkoxy to hydroxy without touching the rest of the molecule.
  • hydrolysis is carried out using tribromide boron, in a chlorinated solvent such as dichloromethane, at a temperature close to 20 ° C.
  • the compounds of formula (I) for which R 2 represents an aromatic substituted by -NR 6 R 7 for which R 6 represents an alkyl radical and R 7 represents a hydrogen atom can also be prepared by deprotection of a compound of formula (I) correspondent for which R 2 represents an aromatic substituted by a -N (alk) COOR 8 in which R 8 represents a tert-butyl radical.
  • This reaction is generally carried out by means of hydrochloric acid, in a solvent such as dioxane, at a temperature in the region of 20 ° C.
  • R 5 When R 5 is alkyl, this reaction is generally carried out in the presence of a mineral acid (sulfuric acid for example), at a temperature between 20 ° C. and the boiling point of the reaction medium.
  • a mineral acid sulfuric acid for example
  • this reaction is preferably carried out in the presence of a carbodiimide (1- (3- dimethylaminopropyl) -3-ethylcarbodiimide, N, N'-dicyclohexyl-carbodiimide for example), in an inert solvent such as an amide (dimethylformamide) or a chlorinated solvent (methylene chloride, dichloro-1,2 ethane, chloroform for example ), at a temperature between 0 ° C and the boiling temperature of the reaction mixture.
  • amide dimethylformamide
  • chlorinated solvent methylene chloride, dichloro-1,2 ethane, chloroform for example
  • This reaction is generally carried out in an inert solvent such as an amide (dimethylformamide for example), at a temperature in the region of 20 ° C.
  • an inert solvent such as an amide (dimethylformamide for example)
  • the compounds of formula (I) for which R 2 and / or R 3 and / or R 4 represent an aromatic substituted by hydroxyalkyl in which the alkyl contains a carbon atom can also be prepared by reduction of a compound of formula (I) for which at least one of the substituents R 2 , R 3 , R 4 represents an aromatic substituted by formyl.
  • This reaction is generally carried out using sodium borohydride, in an aliphatic alcohol 1-4C (methanol, ethanol for example), at a temperature in the region of 0 ° C.
  • the compounds of formula (I) for which R 3 and / or R 4 represents an aromatic substituted by -alk-NR 6 R 7 for which alk is an alkyl containing a carbon atom can also be prepared by the action of a compound of formula (I) for which at least one of the substituents R 3 , R 4 represents an aromatic substituted by formyl on an amine HNR 6 R 7 in which R 6 and R 7 have the same meanings as in formula (I).
  • This reaction is generally carried out in an inert solvent such as a chlorinated solvent (dichloroethane for example), at a temperature in the region of 20 ° C. in the presence of sodium triacetoxyborohydride or sodium cyanoborohydride.
  • an inert solvent such as a chlorinated solvent (dichloroethane for example)
  • This reaction is preferably carried out either in the presence of a condensing agent used in peptide chemistry such as a carbodiimide (for example l- (3-dimethylaminopropyl) -3-ethylcarbodiimide, N, N'-dicyclohexylcarbodiimide ) or N, N'-diimidazole carbonyl, in an inert solvent such as an ether (tetrahydrofuran, dioxane for example), an amide (dimethylformamide) or a chlorinated solvent (methylene chloride, 1,2-dichloroethane, chloroform for example) at a temperature between 0 ° C. and the boiling temperature of the reaction mixture, ie after prior bonding of the acid on a TFP type resin of formula:
  • a condensing agent used in peptide chemistry such as a carbodiimide (for example l- (3-dimethylaminopropyl) -3-
  • S represents an aminopolystyrene resin
  • an inert solvent such as dimethylformamide
  • 4-dimethylaminopyridine at a temperature in the region of 20 ° C.
  • the resin bonding is generally carried out within dimethylformamide, in the presence of 4-dimethylaminopyridine and 1,3-diisopropylcarbodiimide, at a temperature in the region of 20 ° C.
  • the compounds of formula (I) for which R : and / or R 3 and / or R 4 represent an aromatic or a heteroaromatic substituted by -CO-NH-NR 6 R 7 can also be prepared by the action of a compound of formula (I) correspondent for which R 2 and / or R 3 and / or R 4 represent an aromatic or a heteroaromatic substituted by -COOR 5 and R 5 represents an alkyl or phenyl radical optionally substituted by halogens, on a hydrazine H 2 N -NR 6 R 7 for which R 6 and R 7 have the same meanings as in formula (I).
  • This reaction is generally carried out in an inert solvent such as dimethylformamide, at a temperature in the region of 20 ° C.
  • the compounds of formula (I) for which R 2 represents an aromatic or a heteroaromatic substituted by -CO-NHR, in which R represents a hydrogen atom and / or R 3 and / or R 4 represents an aromatic or a heteroaromatic substituted by -CO-NR, 0 R n in which R 10 and R n are hydrogen atoms can also be prepared by hydrolysis of a corresponding compound of formula (I) for which R 2 and / or R 3 and / or R 4 represent an aromatic or a heteroaromatic substituted by cyano.
  • This reaction is carried out by any known method making it possible to pass from a nitrile to the corresponding carbamoyl without touching the rest of the molecule.
  • the operation is carried out by means of hydrochloric acid, within acetic acid, at a temperature in the region of 20 ° C.
  • This reaction is generally carried out in an inert solvent such as acetonitrile, in the presence of an alkali metal carbonate (potassium carbonate for example), at a temperature in the region of 20 ° C.
  • an alkali metal carbonate potassium carbonate for example
  • This reaction is generally carried out in an inert solvent such as a ketone (methyl ethyl ketone for example), in the presence of a base such as an alkali metal carbonate (potassium carbonate for example), at the temperature d 'boiling of the reaction medium.
  • an inert solvent such as a ketone (methyl ethyl ketone for example)
  • a base such as an alkali metal carbonate (potassium carbonate for example)
  • R 3 ' and R 4 ' have the same meanings as substituents R ', R ,, R 2 , R 3 and R 4 of formula (I) provided that at least one of the substituents R 3 ', R 4 'represents a substituted aromatic -alk-Cl in which alk represents a alkyl radical on an amine HNR 6 R 7 in which R 6 R 7 have the same meanings as in formula (I).
  • This reaction is generally carried out in an inert solvent such as a chlorinated solvent (dichloromethane for example), optionally in the presence of a nitrogenous base such as dimethylaminopyridine, diisopropylethylamine, at a temperature between 5 and 25 °. vs.
  • a chlorinated solvent dichloromethane for example
  • a nitrogenous base such as dimethylaminopyridine, diisopropylethylamine
  • the compounds of formula (I) for which R represents a chain B, R 'represents a hydrogen atom and R 3 and / or R 4 represents an aromatic substituted by hydroxyalkyl in which the alkyl residue contains 1 carbon atom can also be prepared by the action of diisobutylaluminum hydride on a corresponding compound of formula (I) for which R represents a chain B, R * represents a hydrogen atom and R 3 and / or R 4 represents an aromatic substituted by one or several radicals -COOR 5 in which R 5 is an alkyl radical.
  • This reaction is generally carried out in toluene, at a temperature between -30 ° C and 0 ° C.
  • the compounds of formula (I) for which R 2 represents a phenyl radical substituted by -NR 6 R 7 representing a 1-piperazinyl ring substituted in position -4 by an alkyl radical can also be prepared by the action of a compound of formula ( I) correspondent for which R 2 represents a phenyl radical substituted by a radical -NR 6 R 7 representing a 1-piperazinyl ring on an alk-CHO derivative in which alk represents a straight or branched chain alkyl radical containing 1 to 5 carbon atoms.
  • This reaction is generally carried out in an inert solvent such as a chlorinated solvent (dichoroethane, chloroform for example), in the presence of NaBH (OCOCH 3 ) 3 , at a temperature in the region of 20 ° C.
  • an inert solvent such as a chlorinated solvent (dichoroethane, chloroform for example)
  • NaBH (OCOCH 3 ) 3 NaBH (OCOCH 3 ) 3
  • the compounds of formula (I) for which R 2 represents a phenyl radical substituted by -NR 6 R 7 representing a 1-piperazinyl ring substituted in position -4 by a radical -COOalk can also be prepared by the action of a compound of formula (I) correspondent for which R 2 represents a phenyl radical substituted by a radical -NR 6 R 7 representing a 1 -piperazinyl ring on a derivative of formula Hal-COOalk in which alk represents an alkyl radical and Hal represents a halogen atom and, preferably, a chlorine atom.
  • This reaction is generally carried out in pyridine, at a temperature in the region of 20 ° C.
  • This reaction is generally carried out in an inert solvent such as a chlorinated solvent (dichloromethane for example), at a temperature in the region of 20 ° C.
  • an inert solvent such as a chlorinated solvent (dichloromethane for example)
  • the compounds of formula (I) for which R 2 represents a phenyl radical substituted by a radical -NR 6 R 7 representing a 1 -piperazinyl ring substituted in position -4 by a radical -CO-alk-NR 14 R 15 can also be prepared by the action of a corresponding compound of formula (I) for which R 2 represents a phenyl radical substituted by a radical -NR 6 R 7 representing a 1 -piperazinyl ring with an acid of formula R I5 R 14 N-alk-COOH in which alk represents an alkyl radical and R 14 and R 15 have the same meanings as in formula (I) optionally followed by deprotection of the product for which R 14 is a tert-butoxycarbonyl radical to obtain the compounds for which R 14 is a hydrogen atom.
  • This reaction is generally carried out in an inert solvent such as a chlorinated solvent (dichloroethane for example, at a temperature in the region of 20 ° C.
  • a chlorinated solvent dichloroethane for example
  • the deprotection is carried out by means of formic acid at a temperature close to 20 ° C.
  • the compounds of formula (I) for which R 2 represents a phenyl radical substituted by a radical -NR 6 R 7 representing a 1 -piperazinyl ring substituted in position -4 by a radical -CO-alk in which alk represents a methyl radical can also be prepared by the action of a corresponding compound of formula (I) for which R 2 represents a phenyl radical substituted by a radical -NR 6 R 7 representing a ring 1 -piperazinyl with acetic anhydride.
  • This reaction is generally carried out in the presence of pyridine, at a temperature in the region of 20 ° C.
  • protecting groups for the hydroxy function mention may be made of triethylsilyl, tert-butyldimethylsilyl which can be regenerated by means of tetrabutylammonium fluoride or alternatively asymmetric acetals (methoxymethyl, tetrahydropyranyl for example) with regeneration by means of 'hydrochloric acid.
  • protecting groups for the carboxy functions mention may be made of esters (allyl, benzyl for example), oxazoles and 2-alkyl-1,3-oxazolines.
  • Other protective groups which can be used are described by GREENE T.W. et al., Protecting Groups in Organic Synthesis, second edition, 1991, Jonh Wiley & Sons.
  • the compounds of formula (I) can be purified by the usual known methods, for example by crystallization, chromatography or extraction.
  • the enantiomers of the compounds of formula (I) can be obtained by splitting the racemates for example by chromatography on a chiral column according to
  • the compounds of formula (I) can optionally be converted into addition salts with a mineral or organic acid by the action of such an acid within an organic solvent such as an alcohol, a ketone, an ether or a solvent chlorine. These salts are also part of the invention.
  • salts may be cited: benzenesulfonate, hydrobromide, hydrochloride, citrate, ethanesulfonate, fumarate, gluconate, iodate, isethionate, maleate, methanesulfonate, methylene-bis- ⁇ -oxynaphtoate, nitrate, oxalate, pamoate, phosphate, salicylate, succinate, sulfate, tartrate, theophyllinacetate and p-toluenesulfonate.
  • the compounds of formula (I) have interesting pharmacological properties. These compounds have a strong affinity for cannabinoid receptors and particularly those of the CB 1 type. They are antagonists of the CB 1 receptor and are therefore useful in the treatment and prevention of disorders affecting the central nervous system, the immune system, the system cardiovascular or endocrine, respiratory, gastrointestinal and reproductive disorders (Hollister, Pharm. Rev .; 38, 1986, 1-20, Reny and Sinha, Prog. Drug Res., 36, 71 - 1 14 (1991), Consroe and Sandyk, in Marijuana / Cannabinoids, Neurobiology and Neurophysiology, 459, Murphy L. and Barthe A. Eds, CRC Press, 1992), bacterial, viral and parasitic infections.
  • these compounds can be used for the treatment or prevention of psychoses including schizophrenia, anxiety disorders, depression, epilepsy, neurodegeneration, cerebellar and spinocerebellar disorders, cognitive disorders, head trauma, panic attacks, peripheral neuropathy, glaucoma, migraine, Parkinson's disease, Alzheimer's disease, Huntington's chorea, Raynaud's syndrome, tremors, compulsive disorder - obsessive, senile dementia, thymic disorders, Tourette syndrome, tardive dyskinesia, bipolar disorders- res, cancer, drug induced movement disorders, dystonia, endotoxic shock, hemorrhagic shock, hypotension, insomnia, immunological diseases, multiple sclerosis, vomiting, asthma, appetite disorders (bulimia, anorexia), obesity, memory disorders, in withdrawal from chronic treatments and abuse of alcohol or drugs (opioids, barbiturates, cannabis, cocaine , amphetamine, phencyclide, hallucinogens, benzodiazepines for example), as analgesics
  • the affinity of the compounds of formula (I) for cannabis receptors was determined according to the method described by KUSTER J.E., STEVENSON J.I., WARD S.J., D'AMBRA T.E., HAYCOCK D.A. in J. Pharmacol. Exp. Ther., 264 1352-1363 (1993).
  • the IC50 of the compounds of formula (I) is less than or equal to 100 nM.
  • the ED50 of the compounds of formula (I) is less than or equal to 50 mg / kg.
  • the compounds of formula (I) have a low toxicity. Their LD50 is greater than 40 mg / kg subcutaneously in mice.
  • R represents a chain (A) or (B) and R ′ represents a hydrogen atom or a -COalk radical, R represents a methyl or ethyl radical,
  • R 2 represents either an aromatic chosen from phenyl and naphthyl, these aromatics being unsubstituted or substituted by one or more halogen, alkyl, alkoxy, hydroxy, -COOR 5 , trifluoromethyl, trifluoromethylsulfanyl, trifluoromethoxy, -NR 6 R 7 , -CO- NH-NR 6 R 7 , cyano, -CONHR ,, alkylsulfanyl, hydroxyalkyl, nitro, -CO-NR l6 R 17 , -O-alkNR 12 R 13 or alkylthioalkyl or a heteroaromatic chosen from isoquinolyl, pyridyl, quinolyl, 1,2 , 3,4-tetrahydroisoquinolyle, 1,2,3,4- tetrahydroquinolyl, thienyl, these heteroaromatics being unsubstituted or substituted by halogen, alkyl,
  • R 3 and R 4 identical or different, represent either an aromatic chosen from phenyl or naphthyl, these aromatics being unsubstituted or substituted by one or more halogen, alkyl, alkoxy, trifluoromethyl, trifluoromethoxy, -CONR 10 R ⁇ , -alk- NR 6 R 7 , hydroxyalkyl, formyl, -COOR 5 , or a heteroaromatic chosen from thiazolyl or thienyl rings, these heteroaromatics being unsubstituted or substituted by halogen, alkyl, alkoxy, -CONR ] 0 R U , -alk-NR 6 R 7 , hydroxyalkyl or -COOR 5 .
  • R 5 is alkyl or phenyl optionally substituted by one or more halogen
  • R 6 and R 7 identical or different, represent a hydrogen atom or an alkyl, -COOalk, cycloalkyl, alkylcycloalkyl, -alk-O-alk, hydroxyalkyl radical or else R 6 and R 7 form together with the atom nitrogen to which they are attached a saturated or unsaturated mono or bicyclic heterocycle having 3 to 10 members, optionally containing another heteroatom chosen from oxygen, sulfur and nitrogen and being optionally substituted by one or more alkyl radicals, -COalk, -COOalk, -CO -NHalk, -CS-NHalk, -CO-alk-NR l4 R, 5 , oxo, hydroxyalkyle, -alk-O-alk, -CO-NH 2 , R represents a hydrogen atom or an alkyl or alkyl radical substituted by dialkylamino, phenyl, cycloalkyl (optionally substituted by -COOalk,
  • R 10 and R represent a hydrogen atom or an alkyl radical or else R 10 and R n together with the nitrogen atom to which they are attached form a saturated mono or bicyclic heterocycle having 3 to 10 links, optionally containing another heteroatom chosen from oxygen, sulfur and nitrogen and being optionally substituted by an alkyl radical,
  • R 12 and R 13 identical or different, represent a hydrogen atom or an alkyl or cycloalkyl radical, or else R 12 and R 13 form together with the nitrogen atom to which they are attached a saturated mono or bicyclic heterocycle having 3 with 10 links, optionally containing another heteroatom chosen from oxygen, sulfur and nitrogen and being optionally substituted by an alkyl radical, -COalk, -COOalk, -CO-NHalk, -CS-NHalk, -CO-alk-NR 14 R 15 or a saturated mono or bicyclic heterocycle having 3 to 10 members and containing a heteroatom chosen from oxygen, sulfur and nitrogen,
  • R, 4 and R 15 identical or different, represent a hydrogen atom or an alkyl or -COOalk radical
  • R 16 and R 17 together with the nitrogen atom to which they are attached form a saturated mono or bicyclic heterocycle having 3 to 10 links, optionally containing another heteroatom chosen from oxygen, sulfur and nitrogen,
  • alk represents an alkyl or alkylene radical
  • the particularly preferred compounds of formula (I) are those for which R represents a chain (A) or (B),
  • R ' representing a hydrogen atom or a radical -COalk
  • R represents a methyl or ethyl radical
  • R 2 represents either an aromatic chosen from
  • phenyl substituted by one or more halogen, alkyl, alkoxy, hydroxy, -COOR 5 (in which R 5 represents an alkyl or phenyl radical optionally substituted by several halogens), trifluoromethyl, trifluoromethylsulfanyl, trifluoromethoxy, -NR 6 R 7 (in which R 6 and R 7 , identical or different, represent a hydrogen atom or an alkyl radical or -COOalk or else R 6 and R 7 form, together with the nitrogen atom to which they are attached, a heterocycle chosen from pyrrolidinyl, piperidyl, piperazinyl or piperazinyl substituted by one or more alkyl radicals, -COalk, -COOalk, -CO-NHalk, -CS-NHalk, -CO-alk-NR 14 R 15 , in which R, 4 and R, 5 , identical or different, represent a hydrogen atom or an alkyl radical),
  • R 3 and R 4 identical or different, represent either an aromatic chosen from
  • alk represents an alkyl or alkylene radical
  • R 2 is a substituted phenyl radical
  • the latter is monosubstituted and, in particular, in position 3 or else disubstituted and, in particular, in positions 3.5; 2.5 or 2.3.
  • R 3 is a substituted phenyl radical
  • the latter is monosubstituted and, in particular, in position 4 or disubstituted and, in particular, in positions 2,4.
  • R 4 is a substituted phenyl radical
  • the latter is monosubstituted and, in particular, in position 4 or disubstituted and, in particular, in positions 2,4.
  • R 4 is a substituted phenyl radical
  • the latter is monosubstituted and, in particular, in position 4 or disubstituted and, in particular, in positions 2,4.
  • Example 1 To a solution of 1 g of 1-benzhydryl-3 - [(methylsulfonyl) (phenyl) methyl- (RS)] azetidin-3-ol in 10 cm 3 of pyridine, cooled to 5 ° C., 0 is added, 3 cm 3 of methanesulfonyl chloride. The mixture is stirred for 2 hours at 5 ° C. and then 1 g of 4-dimethylamino pyridine in 10 cm 3 of dichloromethane is added at 5 ° C. The solution is stirred for 15 hours at room temperature and then concentrated to dryness under reduced pressure (2.7 kPa).
  • the residue obtained is chromatographed on a column of silica gel (particle size 0.04-0.06 mm, diameter 3 cm, height 25 cm), eluting under a pressure of 0.5 bar of nitrogen with dichloromethane and collecting fractions of 80 cm 3 . Fractions 17 to 20 are combined and then concentrated to dryness under reduced pressure (2.7 kPa). The residue is crystallized from 10 cm 3 of ethyl ether. 0.14 g of l-benzhydryl-3- [(methylsulfonyl) (phenyl) methylene] azetidine is obtained, melting at 210 ° C.
  • L-Benzhydryl-3 - [(methylsulfonyl) (phenyl) methyl- (RS)] azetidin-3-ol can be obtained in the following way: in a solution of 1.4 cm 3 of diisopropylamine in 10 cm 3 of tetrahydrofuran , under an argon atmosphere, cooled to 0 ° C., 6.25 cm 3 of n-butyl lithium 1.6N in solution in hexane is added and then cooled to -70 ° C. Then a mixture of 1.7 g of benzyl methyl sulfone in 30 cm 3 of tetrahydrofuran is added and stirring is continued for 45 minutes at -70 ° C.
  • Example 2 Operating according to the procedure of Example 1, starting with 1.9 g of 1 -benzhydryl- 3 - [(3-methylphenyl) (methylsulfonyl) methyl- (RS)] azetidin-3-ol, of 0.52 cm 3 of methanesulfonyl chloride and 1.7 g of 4-dimethylaminopyridine, the residue obtained is purified by chromatography on a column of silica gel (particle size 0.04-0.06 mm, diameter 3 cm, height 17 cm) under a pressure of 0.5 bar of nitrogen with dichloromethane then a mixture of dichloromethane and ethanol (98.5 / 1.5 by volume) as eluents and collecting fractions of 100 cm 3 .
  • the 1 -benzhydryl-3 - [(3-methylphenyl) (methylsulfonyl) methyl- (RS)] azetidin-3-ol can be obtained in the following way: by operating according to the procedure of Example 1 starting from 2 0.8 g of methyl (3-methylbenzyl) sulfone and 3.6 g of 1-benzhydryl azetidin-3-one, obtained after purification on a column of silica gel (particle size 0.04-0.06 mm, diameter 3 cm, height 25 cm) under a pressure of 0.5 bar of nitrogen with a mixture of dichloromethane and ethanol (98.5 / 1.5 by volume) as eluent, 2.6 g of a solid.
  • Methyl (3-methylbenzyl) sulfone can be prepared as follows: to a solution of 30 cm 3 of water, 30 cm 3 of acetic acid and 15 cm 3 of 36N sulfuric acid, the following are added at room temperature , 10.5 g of oxone R then 2.6 g of methyl (3-methyl-benzyl) sulfide and 30 cm 3 of ethanol. The mixture is stirred for 48 hours at room temperature and then taken up in 100 cm 3 of water and 100 cm 3 of ethyl acetate. The organic phase is washed with a saturated aqueous solution of sodium bicarbonate, decanted, dried over magnesium sulfate and concentrated to dryness under reduced pressure (2.7 kPa). 2.8 g of methyl (3-methylbenzyl) sulfone are obtained in the form of a gum.
  • Methyl (3-methylbenzyl) sulfide can be prepared as follows: to a solution of 3.7 g of 3-methylbenzyl bromide in 25 cm 3 of dimethylformamide, the temperature is added below 30 ° C, 1 , 7 g of sodium methylthiolate. The mixture is stirred for 2 hours at a temperature close to 20 ° C. and then taken up in 50 cm 3 of ethyl acetate. The organic phase is washed with 3 times 100 cm 3 of water, dried over magnesium sulfate and concentrated to dryness under reduced pressure (2.7 kPa). 2.6 g of methyl (3-methylbenzyl) sulphide are obtained in the form of an oil.
  • the 1 -benzhydryl-3 - [(4-methylphenyl) (methylsulfonyl) methyl- (RS)] azetidin-3-ol can be obtained in the following way: by operating according to the procedure of the example 1 from 4 g of methyl (4-methylbenzyl) sulfone and 5.1 g of 1-benzhydryl azetidin-3-one, 3 g of l-benzhydryl-3 - [(4-methylphenyl) (methylsulfonyl) methyl are obtained - (RS)] azetidin-3-ol melting at 226 ° C.
  • the methyl (4-methylbenzyl) sulfone can be prepared in the following manner: by operating according to the procedure of Example 2 starting from 3.5 g of methyl (4-methyl-benzyl) sulfide and 12.3 g of oxone R , 3.5 g of methyl (4-methylbenzyl) sulfone are obtained in the form of a solid.
  • Methyl (4-methylbenzyl) sulfide can be prepared in the following manner: by operating according to the procedure of Example 2 from 5.6 g of 4-methylbenzyl bromide and 2.3 g of sodium methyl thiolate , 4.7 g of methyl (4-methylbenzyl) sulfide are obtained in the form of a solid.
  • the residue obtained is chromatographed on a column of silica gel (particle size 0.04-0.06 mm, diameter 3 cm, height 25 cm), eluting under a pressure of 0.5 bar of nitrogen with dichloromethane and then with a mixture of dichloromethane and ethanol (mixture 99/1 by volume) and collecting 100 cm 3 fractions. Fractions 6 to 17 are combined and then concentrated to dryness under reduced pressure (2.7 kPa). The solid obtained is crystallized from 50 cm 3 of ethyl ether.
  • the 1 -benzhydryl-3 - [(2-methylphenyl) (methylsulfonyl) methyl- (RS)] azetidin-3-ol can be obtained in the following manner: by operating according to the procedure of Example 1 from 3 , 4 g of methyl (2-methylbenzyl) sulfone and 4.3 g of 1 -benzhydryl azetidin-3-one, 3.4 g of l-benzhydryl-3 - [(2-methylphenyl) ( methylsulfonyl) methyl- (RS)] azetidin-3-ol melting at 218 ° C.
  • the methyl (2-methylbenzyl) sulfone can be prepared in the following manner: by operating according to the procedure of Example 2 from 4.5 g of methyl (2-methyl-benzyl) sulfide and 16.2 g of 'oxone R , 3.4 g of methyl (2-methylbenzyl) sulfone are obtained in the form of a solid.
  • Methyl (2-methylbenzyl) sulfide can be prepared in the following manner: by operating according to the procedure of Example 2 from 5.6 g of 2-methylbenzyl bromide and 2.1 g of sodium methyl thiolate , 4.5 g of methyl (2-methylbenzyl) sulfide are obtained in the form of a solid.
  • Example 4 By operating according to the procedure of Example 4 starting from 2.1 g of 1-benzhydryl- 3 - [(2-chlorophenyl) (methylsulfonyl) methyl- (RS)] azetidin-3-ol, of 0.55 cm 3 of methanesulfonyl chloride and 2.3 g of 4-dimethylaminopyridine, the residue obtained is purified by chromatography on a column of silica gel (particle size 0.04-0.06 mm, diameter 3 cm, height 25 cm) under a pressure of 0.5 bar of nitrogen with dichloromethane as eluent and collecting 100 cm 3 fractions. Fractions 12 to 18 are combined and concentrated to dryness under reduced pressure (2.7 kPa).
  • the solid obtained is crystallized from a mixture of 3 cm 3 of dichloromethane and 40 cm 3 of ethyl ether. 1.1 g of l-benzhydryl-3 - [(2-chlorophenyl) (methylsulfonyl) methylene] azetidine are obtained, melting at 204 ° C.
  • the 1 -benzhydryl-3 - [(2-chlorophenyl) (methylsulfonyl) methyl- (RS)] azetidin-3-ol can be obtained in the following manner: by operating according to the procedure of Example 1 from 4 g of (2-chlorobenzyl) methylsulfone and 4.6 g of 1-benzhydryl azetidin-3-one, the residue obtained is taken up in 50 cm 3 of ethyl acetate, filtered and dried. 2.4 g of l-benzhydryl-3 - [(2-chlorophenyl) (methylsulfonyl) methyl- (RS)] azetidin-3-ol are obtained in the form of a white solid.
  • (2-Chlorobenzyl) methylsulfone can be prepared in the following manner: by operating according to the procedure of Example 2, starting from 3.4 g of (2-chlorohen__yl) methylsulfide and 12 g of oxone ⁇ on obtains 4 g of (2-chlorobenzyl) methylsulfone in the form of an oil which crystallizes.
  • (2-Chlorobenzyl) methylsulfide can be prepared in the following manner: by operating according to the procedure of Example 2 from 4 g of 2-chlorobenzyl bromide and 1.5 g of sodium methyl thiolate, 3.4 g of (2-chlorobenzyl) methylsul_ure in the form of an oil.
  • the 1 -benzhydryl-3 - [(3-chlorophenyl) (methylsulfonyl) methyl- (RS)] azetidin-3-ol can be obtained in the following manner: by operating according to the procedure of Example 1 from 3 , 1 g of (3-chlorobenzyl) methylsulfone and 3.4 g of 1 -benzhydryl azetidin-3-one, 3.4 g of l-benzhydryl-3 - [(3-chlorophenyl) (methylsulfonyl) are obtained ) methyl- (RS)] azetidin-3-ol as a white solid.
  • (3-chlorobenzyl) methylsulfone can be prepared in the following manner: by operating according to the procedure of Example 2, starting from 3.2 g of (3-chlorobenzyl) methylsulfide and 12 g of oxone ⁇ on 3.2 g of (3-chlorobenzyl) methylsulfone is obtained in the form of a white solid.
  • (3-Chlorobenzyl) methylsulfide can be prepared in the following manner: by operating according to the procedure of Example 2 from 4 g of 3-chlorobenzyl bromide and 1.5 g of sodium methyl thiolate, 3.2 g of 3-chlorobenzyl methyl sulfide in the form of an oil.
  • the solid obtained is crystallized from a mixture of 3 cm 3 and 30 cm 3 of ethyl ether.
  • 0.5 g of l-benzhydryl-3 - [(4-chlorophenyl) (methylsulfonyl) methylene] azetidine is obtained, melting at 192 ° C.
  • the 1 -benzhydryl-3 - [(4-chlorophenyl) (methylsulfonyl) methyl- (RS)] azetidin-3-ol can be obtained in the following manner: by operating according to the procedure of Example 1 from 2 , 8 g of (4-chlorobenzyl) methyl sulfone and 3.24 g of 1-benzhydryl azlit- din-3-one, is obtained after crystallization in 80 cm 3, 3.4 g of l-benzhydryl-3 - [(4 - chlorophenyl) (methylsulfonyl) methyl- (RS)] azetidin-3-ol in the form of a white solid.
  • (4-chlorobenzyl) methylsulfone can be prepared in the following manner: by operating according to the procedure of Example 2, starting with 3.5 g of (4-chlorobenzyl) methylsulfide and 12.3 g of oxone , 3.5 g of (4-chlorobenzyl) methylsulfone are obtained in the form of a solid.
  • Example 4 By operating according to the procedure of Example 4 starting from 3.1 g of 1-benzhydryl- 3 - [(3,5-dichlorophenyl) (methylsulfonyl) methyl- (RS)] azetidin-3-ol, from 0 , 75 cm 3 of methanesulfonyl chloride and 3.1 g of 4-dimethylaminopyridine, the residue obtained is purified by chromatography on a column of silica gel (particle size 0.04-0.06 mm, diameter 3 cm, height 25 cm) under a pressure of 0.5 bar of nitrogen with dichloromethane as eluent and collecting 100 cm 3 fractions.
  • silica gel particle size 0.04-0.06 mm, diameter 3 cm, height 25 cm
  • the 1 -benzhydryl-3 - [(3,5-dichlorophenyl) (methylsulfonyl) methyl- (RS)] azetidin-3-ol can be obtained in the following way: by operating according to the procedure of Example 1 starting from 4 g of (3,5-dichlorobenzyl) methylsulfone and 4 g of 1-benzhy- drylazlit-3-one, 3.2 g t of l-benzhydryl-3 - [(3,5-dichlorophenyl nyl) (methylsulphonyl) methyl- (RS)] azetidin-3-ol as a solid White.
  • the (3,5-dichlorobenzyl) methylsulfone can be prepared in the following manner: by operating according to the procedure of Example 2, starting with 5.3 g of (3,5-dichlorobenzyl) methylsulphide and 17 g of oxone R , 5 g of (3,5-dichlorobenzyl) methylsulfone are obtained in the form of a white solid.
  • (3,5-Dichlorobenzyl) methylsulfide can be prepared in the following manner: by operating according to the procedure of Example 2 from 5 g of 3,5-dichlorobenzyl chloride and 2 g of sodium methyl thiolate, 5.3 g of (3,5-dichlorobenzyl) methylsulfide are obtained in the form of an oil.
  • Example 4 By operating according to the procedure of Example 4 starting from 5 g of 1 -benzhydryl- 3 - [(3,4-dichlorophenyl) (methylsulfonyl) methyl- (RS)] azetidin-3-ol, 1.2 cm 3 of methanesulfonyl chloride and 3.8 g of 4-dimethylaminopyridine, the residue obtained is purified by chromatography on a column of silica gel (particle size 0.04-0.06 mm, diameter 4 cm, height 35 cm) under a pressure of 0.5 bar of nitrogen with a cyclohexane and ethyl acetate mixture (70/30 by volume) as eluent and collecting 35 cm 3 fractions.
  • silica gel particle size 0.04-0.06 mm, diameter 4 cm, height 35 cm
  • the 1 -benzhydryl-3 - [(3,4-dichlorophenyl) (methylsulfonyl) methyl- (RS)] azetidin-3-ol can be obtained in the following way: by operating according to the procedure of Example 1 starting from 4.5 g of (3,4-dichlorobenzyl) methylsulfone and 4.3 g of 1-benzhydryl azetidin-3-one, 5 g of l-benzhydryl-3 - [(3,4-dichlorophenyl) (methylsulfonyl) methyl- (RS)] azetidin-3-ol are obtained in the form of a solid White.
  • (3,4-Dichlorobenzyl) methylsulfone can be prepared in the following manner: by operating according to the procedure of Example 2, starting from 4.3 g of (3,4-dichlorobenzyl) methylsulfide and 13 g of oxone ⁇ 4.7 g of (3,4-dichlorobenzyl) methylsulfone are obtained in the form of a white solid.
  • (3,4-Dichlorobenzyl) methylsulfide can be prepared in the following manner: by operating according to the procedure of Example 2 from 2.8 cm 3 of 3,4-dichlorobenzyl chloride and 1.5 g of sodium methyl thiolate, 4.3 g of (3,4-dichlorobenzyl) methylsulfide are obtained in the form of an oil.
  • L-Benzhydryl-3 - [(2,5-dichlorophenyl) (methylsulfonyl) methyl- (RS)] azetidin-3-ol can be obtained in the following way: by operating according to the procedure of Example 1 from 1.2 g of (2,5-dichlorobenzyl) methylsulfone and 1.2 g of 1 -benzhydryl azetidin-3-one, 1.8 g of l-benzhydryl-3 - [( 2,5-dichlorophenyl) (methylsulfonyl) methyl- (RS)] azetidin-3-ol in the form of a white solid.
  • (2,5-Dichlorobenzyl) methylsulfone can be prepared as follows: 1.9 g of sodium methanesulfinate are added at room temperature to a solution of 2.7 g of 2,5-dichlorobenzyl chloride in 30 cm 3 of ethanol. The mixture is heated at reflux for 5 hours, cooled to room temperature and then taken up in 50 cm 3 of water and 50 cm 3 of ethyl acetate. The organic phase is decanted, washed with 20 cm 3 of an aqueous solution saturated with sodium chloride, dried over magnesium sulphate and concentrated to dryness under reduced pressure (2.7 kPa). 1.2 g of (2,5-dichlorobenzyl) methylsulfone are obtained in the form of a white solid.
  • 1-Benzhydryl-3 - [(2,4-dichlorophenyl) (methylsulfonyl) methyl- (RS)] azetidin-3-ol can be obtained in the following manner: by operating according to the procedure of Example 1 starting from 4.8 g of (2,4-dichlorobenzyl) methylsulfone and 4.7 g of 1 -benzhydryl azetidin-3-one, 9.1 g of l-benzhydryl-3 - [(2,4-dichlorophenyl) (methylsulfonyl) methyl- (RS)] azetidin-3-ol are obtained a brown meringue.
  • (2,4-Dichlorobenzyl) methylsulfone can be prepared in the following manner: by operating according to the procedure of Example 2, starting with 4 g of (2,4-dichlorobenzyl) methylsulfide and 13 g of oxone R , 4.8 g of (2,4-dichlorobenzyl) methylsulfone are obtained in the form of a white solid, melting at 111 ° C.
  • the (2,4-dichloroben__yl) methylsul_ure can be prepared in the following way: by operating according to the procedure of Example 2 from 2.8 cm 3 of 2,4-dichlorobenzyl chloride and 1.5 g of sodium methylthiolate, 4 g of (2,4-dichlorobenzyl) methylsulfide are obtained in the form of an oil.
  • 1-Benzhydryl-3 - [(2,3-dichlorophenyl) (methylsulfonyl) methyl- (RS)] azetidin-3-ol can be obtained in the following manner: by operating according to the procedure of Example 1 starting from 3.6 g of (2,3-dichlorobenzyl) methylsulfone and 3.6 g of 1-benzhydryl azetidin-3-one, 5.4 g of l-benzhydryl-3 - [(2,3-dichlorophenyl) (methylsulfonyl) methyl- (RS)] azetidino-3-ol are obtained a solid white.
  • the (2,3-dichlorobenzyl) methylsulfone can be prepared in the following manner: by operating according to the procedure of Example 10 from 3 g of 2,3-dichlorobenzyl chloride and 2.4 g of sodium methanesulfinate , 3.6 g of (2,3-dichlorobenzyl) methylsulfone are obtained in the form of a white solid.
  • 1-Benzhydryl-3 - [(3-fluorophenyl) (methylsulfonyl) methyl- (RS)] azetidin-3-ol can be obtained in the following manner: by operating according to the procedure of Example 1, starting from 2 , 6 g of 3-fluorobenzyl methyl sulfone and 3.3 g of 1-benzhydryl azetidin-3-one, 2.9 g of l-benzhydryl-3 - [(3-fluorophenyl) (methylsulfonyl) methyl- are obtained RS)] azetidin-3-ol as a white solid, melting at 200 ° C.
  • 3-fluorobenzyl methyl sulfone can be prepared in the following manner: by operating according to the procedure of Example 2 starting from 3.1 g of 3-fluorobenzyl methyl thyl sulfide and 13 g of oxone R , 2.7 g of 3-fluorobenzyl methyl sulfone are obtained in the form of a white solid.
  • 3-fluorobenzyl methyl sulfide can be prepared in the following manner: by operating according to the procedure of Example 2, starting with 2.6 cm 3 of 3-fluorobenzyl bromide and 1.6 g of sodium methyl thiolate, 3.1 g of 3-fluorobenzyl methyl sulfide are obtained in the form of an oil.
  • the solid obtained is crystallized from 100 cm 3 of ethyl ether. 2.3 g of 1 -benzhydryl-3 - [(2-fluorophenyl) (methylsulfonyl) methylene] azetidine are obtained, melting at 188 ° C.
  • 1-Benzhydryl-3 - [(2-fluorophenyl) (methylsulfonyl) methyl- (RS)] azetidin-3-ol can be obtained in the following manner: by operating according to the procedure of Example 1 from 3 , 4 g of 2-fluorobenzyl methyl sulfone and 4.2 g of 1 -benzhydryl azetidin- 3-one, 4.3 g of l-benzhydryl-3 - [(3-fluorophenyl) (methylsulfonyl) methyl- are obtained )] azetidin-3-ol as a white solid.
  • the 2-fluorobenzyl methyl sulfone can be prepared in the following manner: by operating according to the procedure of Example 2 from 3 g of 2-fluorobenzyl methyl sulfide and 13 g of oxone R , 3.6 g of 3-fluorobenzyl methyl sulfone are obtained in the form of a white solid.
  • the 2-fluorobenzyl methyl sulfide can be prepared in the following manner: by operating according to the procedure of Example 2 from 2.4 cm 3 of 2-fluorobenzyl bromide and 1.5 g of sodium methyl thiolate, 3 g of 2-fluorobenzyl methyl sulfide are obtained in the form of an oil.
  • 1-Benzhydryl-3 - [(4-fluorophenyl) (methylsulfonyl) methyl- (RS)] azetidin-3-ol can be obtained in the following manner: by operating according to the procedure of Example 1, starting from 2 , 8 g of 4-fluorobenzyl methyl sulfone and 3.6 g of 1-benzhydryl azetidin-3-one, 1 g of l-benzhydryl-3 - [(4-fluorophenyl) (methylsulfonyl) methyl- (RS)] is obtained azetidin-3-ol as a white solid.
  • 4-fluorobenzyl methyl sulfone can be prepared in the following manner: by operating according to the procedure of Example 2 from 3 g of 4-fluorobenzyl methyl sulfide and 13 g of oxone R , 3 g of 4-fluorobenzyl methyl sulfone are obtained in the form of a white solid, melting at 110 ° C.
  • the 4-fluorobenzyl methyl sulfide can be prepared in the following manner: by operating according to the procedure of Example 2 from 2.5 cm 3 of 4-fluorobenzyl chloride and 1.5 g of sodium methyl thiolate, 3 g of 4-fluorobenzyl methyl sulfide are obtained in the form of an oil.
  • the 1 -benzhydryl-3 - [(3,5-difluorophenyl) (methylsulfonyl) methyl- (RS)] azetidin-3-ol can be obtained in the following way: by operating according to the procedure of Example 1 starting from 3.2 g of 3,5-difluorobenzyl methyl sulfone and 3.7 g of 1-benzhydryl azetidin-3-one, 3.9 g of l-benzhydryl-3 - [(3,5-difluorophenyl) are obtained ) (methylsulfonyl) methyl- (RS)] azetidin-3-ol as a white solid.
  • 3,5-difluorobenzyl methyl sulfone can be prepared in the following way: by operating according to the procedure of example 2 starting from 4.2 g of 3,5-difluorobenzyl methyl sulfide and 16 g of oxone R , 3.3 g of 3,5-difluorobenzyl methyl sulfone are obtained in the form of a white solid.
  • 3,5-difluorobenzyl methyl sulfide can be prepared in the following way: by operating according to the procedure of example 2 starting from 5 g of 3,5-difluorobenzyl bromide and 2 g of sodium methyl thiolate, obtains 4.9 g of 3,5-difluorobenzyl methyl sulfide in the form of an oil.
  • the 1 -benzhydryl-3 - [(2,3-difluorophenyl) (methylsulfonyl) methyl- (RS)] azetidin-3-ol can be obtained in the following way: by operating according to the procedure of Example 1 starting from 4 g of (2,3-difluorobenzyl) methylsulfone and 4.8 g of 1 -benzhydryl azetidin-3-one, 5.5 g of l-benzhydryl-3 - [(2,3-difluorophenyl) are obtained (methylsulfonyl) methyl- (RS)] azetidin-3-ol in the form of a beige solid.
  • (2,3-Difluorobenzyl) methylsulfone can be prepared in the following manner: by operating according to the procedure of Example 10 from 4.1 g of bromide 2,3-difluorobenzyl and 4.1 g of sodium methanesulfinate, 4 g of (2,3-difluorobenzyl) methyl sulfone are obtained in the form of a white solid.
  • 1-Benzhydryl-3 - [(2,5-difluorophenyl) (methylsulfonyl) methyl- (RS)] azetidin-3-ol can be obtained in the following way: by operating according to the procedure of Example 1 starting from 4 g of (2,5-difluorobenzyl) methyl sulfone and 4.8 g of 1-benzhydryl azetidin-3-one, 5.9 g of l-benzhydryl-3 - [(2,5-difluorophenyl) are obtained ) (methylsulfonyl) methyl- (RS)] azetidin-3-ol as a creamy white solid.
  • the (2,5-difluorobenzyl) methyl sulfone can be prepared in the following manner: by operating according to the procedure of Example 10 from 4.1 g of 2,5-difluorobenzyl bromide and 4.1 g of sodium methanesulfinate, 4.8 g of (2,5-difluorobenzyl) methyl sulfone are obtained in the form of a white solid, melting at 95 ° C.
  • Example 4 Operating according to the procedure of Example 4 starting from 7.7 g of 1 -benzhydryl- 3 - [(3-bromophenyl) (methylsulfonyl) methyl- (RS)] azetidin-3-ol, 1.8 cm 3 of methanesulfonyl chloride and 5.8 g of 4-difhylaminopyridine, the residue obtained is purified by chromatography on a column of silica gel (particle size 0.04- 0.06 mm, diameter 3 cm, height 35 cm) under a pressure of 0.5 bar of nitrogen with dichloromethane and then a mixture of dichloromethane and ethanol (99.5 / 0.5 by volume) as eluents and collecting fractions of 100 cm 3 .
  • the 1 -benzhydryl-3 - [(3-bromophenyl) (methylsulfonyl) methyl- (RS)] azetidin-3-ol can be obtained in the following manner: by operating according to the procedure of Example 1 starting from 8 g of 3-bromobenzyl methyl sulfone and 7.6 g of 1 -benzhydryl azetidin- 3-one, 8 g of l-benzhydryl-3 - [(3-bromophenyl) (methylsulfonyl) methyl- (RS)] are obtained 3-ol as a white solid.
  • 3-bromobenzyl methyl sulfone can be prepared in the following manner: by operating according to the procedure of Example 2 starting from 9 g of 3-bromobenzyl methyl sulfide and 27 g of oxone R , 8.2 g are obtained of 3-bromobenzyl methyl sulfone in the form of a white solid.
  • the 3-bromobenzyl methyl sulfide can be prepared in the following way: by operating according to the procedure of Example 2 from 10 g of 3-bromobenzyl bromide and 3.1 g of sodium methyl thiolate, 9 are obtained. g of 3-bromobenzyl methyl sulfide in the form of an oil.
  • Example 4 Operating according to the procedure of Example 4, starting with 1.5 g of 1-benzhydryl- 3 - [(3-iodophenyl) (methylsulfonyl) methyl- (RS)] azetidin-3-ol, of 0.3 cm 3 of chloride of methanesulfonyl and 1.4 g of 4-dimethylaminopyridine, the residue obtained is purified by chromatography on a column of silica gel (particle size 0.04-0.06 mm, diameter 3 cm, height 35 cm) under a pressure of 0, 5 bar of nitrogen with dichloromethane then a mixture of dichloromethane and ethanol (99.7 / 0.3 by volume) as eluents and collecting fractions of 100 cm 3 .
  • the 1 -benzhydryl-3 - [(3-iodophenyl) (methylsulfonyl) methyl- (RS)] azetidin-3-ol can be obtained in the following manner: by operating according to the procedure of Example 1 from 3 , 7 g of 3-iodobenzyl methyl sulfone and 3 g of 1 -benzhydryl azetidin-3- one, 1.5 g of l-benzhydryl-3 - [(3-iodophenyl) (methylsulfonyl) methyl- (RS)] are obtained azetidin-3-ol as a white solid.
  • 3-iodobenzyl methyl sulfone can be prepared in the following way: by operating according to the procedure of Example 2 starting from 3.6 g of 3-iodobenzyl methyl sulfide and 10.3 g of oxone R , one obtains 3.7 g of 3-iodobenzyl methyl sulfone in the form of a white solid.
  • 3-iodobenzyl methyl sulfide can be prepared in the following manner: by operating according to the procedure of Example 2 from 5 g of 3-iodobenzyl bromide and 1.3 g of sodium methyl thiolate, 4 g of 3-iodobenzyl methyl sulfide in the form of an oil.
  • 1-Benzhydryl-3 - [(methylsulfonyl) (3-trifluoromethoxyphenyl) methyl- (RS)] azetidin-3-ol can be obtained in the following way: by operating according to the procedure of Example 1 starting from 2.4 g of methyl (3-trifluoromethoxybenzyl) sulfone and 2.2 g of 1-benzhydryl azetidin-3-one, 2.4 g of l-benzhydryl-3- [(methylsulfonyl) (3-trifluoromethoxyphenyl) are obtained methyl- (RS)] azetidin-3-ol as a white solid.
  • the methyl (3-trifluoromethoxybenzyl) sulfone can be prepared in the following manner: by operating according to the procedure of Example 2, starting from 2.6 g of methyl (3-trifluoromethoxybenzyl) sulfide and 7.2 g of 'oxone R , 2.4 g of methyl (3-trifluoromethoxybenzyl) sulfone are obtained in the form of a white solid.
  • the methyl (3-trifluoromethoxybenzyl) sulfide can be prepared in the following manner: by operating according to the procedure of Example 2 from 3 g of 3-trifluoromethoxybenzyl bromide and 1 g of sodium methyl thiolate, 3 are obtained. , 3 g of methyl (3-tri__uoromethoxybenzyl) sulfide in the form of an oil.
  • Example 22 By operating according to the procedure of Example 4, starting with 4, 1 g of 1 -benzhydryl- 3 - [(methylsulfonyl) (3-trifluoromethylphenyl) methyl- (RS)] azetidin-3-ol, of 1 cm 3 of methanesulfonyl chloride and 4.2 g of 4-dimethylaminopyridine, the residue obtained is purified by chromatography on a column of silica gel (particle size 0.04-0.06 mm, diameter 3 cm, height 35 cm) under a pressure of 0.5 bar of nitrogen with dichloromethane as eluent, collecting 100 cm 3 fractions. Fractions 10 to 14 are combined and concentrated to dryness under reduced pressure (2.7 kPa).
  • the solid obtained is crystallized from a mixture of 2 cm 3 of dichloromethane and 30 cm 3 of ethyl ether. 1.2 g of l-benzhydryl-3 - [(methylsulfonyl) (3-trifluoromethylphenyl) methylene] azetidine are obtained, melting at 178 ° C.
  • 1-Benzhydryl-3 - [(methylsulfonyl) (3-trifluoromethylphenyl) methyl- (RS)] azetidin-3-ol can be obtained in the following way: by operating according to the procedure of Example 1 starting from 3 , 4 g of methyl (3-trifluoromethylbenzyl) sulfone and 3.4 g of 1- benzhydryl azetidin-3-one, 4.2 g of l-benzhydryl-3 - [(methylsulfonyl) (3-trifluoromethylphenyl) methyl- are obtained (RS)] azetidin-3-ol as a white solid.
  • the methyl (3-trifluoromethylbenzyl) sulfone can be prepared in the following manner: by operating according to the procedure of Example 2 from 3.3 g of methyl (3-trifluoromethylbenzyl) sulfide and 10 g of oxone R , 3.4 g of methyl (3-trifluoromethylbenzyl) sulfone are obtained in the form of a white solid.
  • Methyl (3-trifluoromethylbenzyl) sulfide can be prepared in the following manner: by operating according to the procedure of Example 2 from 3.9 g of 3-trifluoromethylbenzyl bromide and 1.4 g of sodium methyl thiolate , 3.3 g of methyl (3-trifluoromethylbenzyl) sulfide are obtained in the form of an oil.
  • Example 23 By operating according to the procedure of Example 4 starting from 2.7 g of del-benzhydryl-3 - ⁇ [3,5-bis (trifluoromethyl) phenyl] (methylsulfonyl) methyl- (RS) ⁇ azetidin-3-ol , 0.6 cm 3 of methanesulfonyl chloride and 2.4 g of 4-dimethylaminopyridine, the residue obtained is purified by chromatography on a column of silica gel (particle size 0.04-0.06 mm, diameter 6 cm, height 40 cm) under a pressure of 0.5 bar of nitrogen with dichloromethane as eluent, collecting fractions of 100 cm 3 .
  • 1-Benzhydryl-3 - ⁇ [3,5-bis (trifluoromethyl) phenyl] (methylsulfonyl) methylene ⁇ azetidin-3-ol can be obtained in the following way: by operating according to the procedure of Example 1 starting from 3.1 g of methyl [3,5- bis (trifluoromethyl) benzyl] sulfone and 2.4 g of 1-benzhydryl azetidin-3-one, 2.8 g of l-benzhydryl-3 - ⁇ 2.8, 5-bis (trifluoromethyl) phenyl] (methylsulfonyl) methylene ⁇ azetidin-3-ol in the form of a white solid.
  • the methyl [3,5-bis (trifluoromethyl) benzyl] sulfone can be prepared in the following manner: by operating according to the procedure of Example 10 from 3 g of 3,5-bis (trifluoromethyl) benzyl chloride and 2 g of sodium methanesulfinate, 3.1 g of methyl [3,5-bis (trifluoromethyl) benzyl] sulfone are obtained in the form of a white solid, melting at 132 ° C.
  • 1-Benzhydryl-3 - [(3,5-dibromophenyl) (methylsulfonyl) methyl- (RS)] azetidin-3-ol can be obtained in the following way: by operating according to the procedure of Example 1 starting from 6.2 g of (3,5-dibromobenzyl) methylsulfone and 4.5 g of 1-ben-zhydryl azetidin-3-one, we obtain 10.7 g of l-benzhydryl-3 - [(3,5- dibromophenyl) (methylsulfonyl) methyl- (RS)] azetidin-3-ol in the form of a meringue.
  • (3,5-Dibromobenzyl) methylsulfone can be prepared in the following manner: by operating according to the procedure of Example 2, starting from 5.8 g of (3,5-dibromobenzyl) methylsulfide and 13 g of oxone R , 6.2 g of (3,5-dibromobenzyl) methylsulfone are obtained in the form of a white solid.
  • (3,5-Dibromobenzyl) methylsulfide can be prepared in the following manner: by operating according to the procedure of Example 2 from 6.6 g of 3,5-dibromobenzyl bromide and 1.5 g of methyl sodium thiolate, 5.8 g of (3,5-dibromobenzyl) methylsulfide are obtained in the form of an oil.
  • the 1 -benzhydryl-3 - [(methylsulfonyl) (3-nitrophenyl) methyl- (RS)] azetidin-3-ol can be obtained in the following way: by operating according to the procedure of Example 1 from 3 , 9 g of methyl (3-nitrobenzyl) sulfone and 4.2 g of 1 -benzhydryl azetidin- 3-one, 4.2 g of 1 -benzhydryl 3 - [(methylsulfonyl) (3-nitrophenyl) methyl- are obtained RS)] azetidin-3-ol in the form of a meringue.
  • the methyl (3-nitrobenzyl) sulfone can be prepared in the following manner: by operating according to the procedure of Example 2 from 18.1 g of methyl (3-nitrobenzyl) sulfide and 68 g of oxone ⁇ 13.9 g of methyl (3-nitrobenzyl) sulfone are obtained in the form of a meringue.
  • the methyl (3-nitrobenzyl) sulfide can be prepared in the following manner: by operating according to the procedure of Example 2 from 17.2 g of 3-nitrobenzyl chloride and 7.7 g of sodium methyl thiolate , 18.2 g of methyl (3-nitrobenzyl) sulfide are obtained in the form of an oil.
  • a mixture of 0.34 g of 1-benzhydryl-3 - [(methylsulfonyl) (3-nitrophenyl) methylene] azetidine, 16 cm 3 of IN hydrochloric acid in 8 cm 3 of ethanol and 16 cm 3 of tetrahydrofuran is heated to reflux. 0.17 g of iron powder is added and the reflux is maintained for 3 hours. The mixture is then cooled to room temperature, the insoluble material is filtered. The solution is taken up in 10 cm 3 of IN sodium hydroxide solution and 50 cm 3 of a saturated aqueous solution of sodium chloride.
  • the aqueous phase is extracted with 3 times 40 cm 3 of dichloromethane, the extracts are combined, dried over sodium sulfate and concentrated to dryness under reduced pressure (2.7 kPa).
  • the residue is purified on a silica gel column (particle size 0.04-0.06 mm, diameter 3 cm, height 30 cm) under a pressure of 0.5 bar of nitrogen with a mixture of cyclohexane and ethyl acetate ( 50/50 by volume) as eluent, collecting 20 cm 3 fractions.
  • Fractions 13 to 31 are combined and concentrated to dryness under reduced pressure (2.7 kPa).
  • the solid obtained is crystallized from 15 cm 3 of ethyl ether.
  • 1-Benzhydryl-3 - [(3-methoxycarbonylphenyl) (methylsulfonyl) methyl- (RS)] azetidin-3-ol can be obtained in the following way: by operating according to the procedure of Example 1 starting from 3 g of (3-methoxycarbonylbenzyl) methyl sulfone and 3.6 g of 1 -benzhydryl azetidin-3-one, obtained after purification by chromatography on a column of silica gel (particle size 0.04-0.06 mm, diameter 3 cm, height 30 cm) under a pressure of 0.5 bar of nitrogen with dichloromethane then a dichloromethane and ethanol mixture (99/1 by volume) as eluents, 1.2 g of l-benzhydryl-3- [(3-methoxycarbonylphenyl) (methylsulfonyl) methyl- (RS)] azetidin-3-ol in the form of a mering
  • the (3-methoxycarbonylbenzyl) methylsulfone can be prepared in the following manner: by operating according to the procedure of Example 2 from 4.3 g of (3-methoxycarbonylbenzyl) methylsulfide and 13.4 g of oxone R , 3.4 g of (3-methoxycarbonylber_zyl) methylsulfone are obtained in the form of a white solid.
  • the (3-methoxycarbonylbenzyl) methylsulfide can be prepared in the following manner: by operating according to the procedure of Example 2 from 5 g of 3-methoxycarbonylbenzyl bromide and 1.7 g of sodium methyl thiolate, 4.3 g of (3-methoxycarbonylbenzyl) methylsulfide in the form of an oil.
  • 1-Benzhydryl-3 - [(3-cyanophenyl) (methylsulfonyl) methyl- (RS)] azetidin-3-ol can be obtained in the following manner: by operating according to the procedure of Example 1 from 3 , 9 g of (3-cyanobenzyl) methylsulfone and 4.7 g of 1 -benzhydryl azetidin- 3-one, 6.2 g of l-benzhydryl-3 - [(3-cyanophenyl) (methylsulfonyl) methyl- are obtained RS)] azetidin-3-ol as a white solid.
  • (3-cyanobenzyl) methylsulfone can be prepared in the following manner: by operating according to the procedure of Example 2 from 6.7 g of (3-cyanobenzyl) methylsulfide and 27.6 g of oxone R , 3.9 g of (3-cyanobenzyl) methylsulfone are obtained in the form of a white solid.
  • the (3-cyanobenzyl) methylsulfide can be prepared in the following manner: by operating according to the procedure of Example 2 from 8 g of 3-cyanobenzyl bromide and 3.1 g of sodium methyl thiolate, 6.8 g of (3-cyanobenzyl) methylsulfide in the form of an oil.
  • the residue is purified by chromatography on a column of silica gel (particle size 0.04-0.06 mm, diameter 3 cm, height 35 cm) under a pressure of 0.5 bar of nitrogen with dichloromethane then a dichloromethane mixture and methanol (99.4 / 0.6 by volume) as eluents and collecting 100 cm 3 fractions. Fractions 13 to 16 are combined and concentrated to dryness under reduced pressure (2.7 kPa). The solid obtained is crystallized from 10 cm 3 of ethyl ether.
  • the solid is washed with 20 cm 3 of a mixture of acetic acid and concentrated hydrochloric acid (50-50 by volume) then with 3 times 20 cm 3 of water and finally with 20 cm 3 of ethanol
  • the solid white obtained is under reduced pressure (2.7 kPa) at 45 ° C and 2.5 g of l-benzhydryl-3 - [(3-carboxyphenyl) (methylsulfonyl) methylene] azetidine hydrochloride are obtained a solid white.
  • the mixture is concentrated to dryness under reduced pressure (2.7 kPa) then the residue is purified by chromatography on co- lonne of silica gel (particle size 0.04-0.06 mm, diameter 3 cm, height 30 cm) under a pressure of 0.5 bar of nitrogen with a mixture of dichloromethane and ethanol (99/1 by volume) then a mixture of dichloromethane and ethanol (98/2 by volume) as eluents and collecting 60 cm 3 fractions. Fractions 18 to 30 are combined and concentrated to dryness under reduced pressure (2.7 kPa).
  • Example 4 By operating according to the procedure of Example 4 starting from 4.6 g of 1 -benzhydryl- 3 - [(3-methoxyphenyl) (methylsulfonyl) methyl- (RS)] azetidin-3-ol, 1.2 cm 3 of methanesulfonyl chloride and 3.8 g of 4-dimethylaminopyridine, after recrystallization from 150 cm 3 of acetonitrile, 2.6 g of l-benzhydryl-3 - [(3-methoxyphenyl) (methylsulfonyl) are obtained ) methylene] azetidine melting at 179 ° C.
  • the 1 -benzhydryl-3 - [(3-methoxyphenyl) (methylsulfonyl) methyl- (RS)] azetidin-3-ol can be obtained in the following manner: by operating according to the procedure of Example 1 from 3 , 4 g of (3-methoxybenzyl) methylsulfone and 4 g of 1 -benzhydryl azetidin-3-one, 4.6 g of l-benzhydryl-3 - [(3-methoxyphenyl) (methylsulfonyl) methyl- are obtained RS)] azetidin-3-ol as a white solid.
  • (3-Methoxybenzyl) methylsulfone can be prepared in the following manner: by operating according to the procedure of Example 2, starting from 3.4 g of (3-methoxybenzyl) methylsulfide and 13 g of oxone ⁇ on obtains 4 g of (3-methoxybenzyl) methylsulfone in the form of a white solid, melting at 71 ° C.
  • (3-Methoxybenzyl) methylsulfide can be prepared in the following manner: by operating according to the procedure of Example 2 from 3.1 g of 3-methoxybenzyl bromide and 1.5 g of sodium methyl thiolate, 3.4 g of (3-methoxybenzyl) methylsulfide are obtained in the form of an oil.
  • L-Benzhydryl-3 - [(4-methoxyphenyl) (methylsulfonyl) methylene] azetidine can be obtained in the following manner: by operating according to the procedure of Example 4 from 3.5 g of l-benzhydryl- 3 - [(4-methoxyphenyl) (methylsulfonyl) methyl- (RS)] azetidin-3-ol, 0.9 cm 3 of methanesulfonyl chloride and 2.9 g of 4-dimethylaminopyridine, the residue obtained is purified by recrystallization in 100 cm 3 of acetonitrile. 1 g of l-benzhydryl-3 - [(4-methoxyphenyl) (methylsulfonyl) methylene] azetidine is obtained, melting at 181 ° C.
  • the 1 -benzhydryl-3 - [(4-methoxyphenyl) (methylsulfonyl) methyl- (RS)] azetidin-3-ol can be obtained in the following manner: by operating according to the procedure of Example 1 from 3 , 5 g of (4-methoxybenzyl) methylsulfone and 4 g of 1 -benzhydryl azetidin-3-one, 3.6 g of l-benzhydryl-3 - [(4-methoxyphenyl) (methylsulfonyl) methyl- are obtained RS)] azetidin-3-ol as a white solid.
  • (4-methoxybenzyl) methylsulfone can be prepared in the following manner: by operating according to the procedure of Example 2, starting from 3.4 g of (4-methoxybenzyl) methylsulfide and 13 g of oxone R , 3.5 g of (3-methoxybenzyl) methylsulfone are obtained in the form of a white solid, melting at 113 ° C.
  • (4-Methoxybenzyl) methylsulfide can be prepared in the following manner: by operating according to the procedure of Example 2, starting from 3.1 g of 4-methoxybenzyl chloride and 1.5 g of sodium methyl thiolate, 3.4 g of (4-methoxybenzyl) methylsulfide are obtained in the form of an oil.
  • Example 34
  • L-Benzhydryl-3 - [(2-methoxyphenyl) (methylsulfonyl) methylene] azetidine can be obtained in the following manner: by operating according to the procedure of Example 4 from 4.2 g of l-benzhydryl- 3 - [(2-methoxyphenyl) (methylsulfonyl) methyl- (RS)] azetidin-3-ol, 1.1 cm 3 of methanesulfonyl chloride and 3.5 g of 4-dimethylaminopyridine, the residue obtained is purified by chromatography on a silica gel column (particle size 0.04-0.06 mm, diameter 4 cm, height 30 cm) under a pressure of 0.5 bar of nitrogen with a mixture of dichloromethane and ethyl acetate (50 / 50 by volume) as eluents and collecting 40 cm 3 fractions.
  • the 1 -benzhydryl-3 - [(2-methoxyphenyl) (methylsulfonyl) methyl- (RS)] azetidin-3 -ol can be obtained in the following way: by operating according to the procedure of Example 1 from 4 g of (2-methoxybenzyl) methylsulfone and 4.5 g of 1-ben- zhydryl azetidin-3-one, 4.3 g of l-benzhydryl-3 - [(2-methoxyphenyl) (methylsulfonyl) methyl- (RS)] azetidin-3-ol are obtained in the form of a brown meringue.
  • the (2-methoxybenzyl) methylsulfone can be prepared in the following manner: by operating according to the procedure of Example 10 from 3.1 g of 2-methoxybenzyl chloride and 4.1 g of sodium methanesulfinate, obtains 4 g of (2-methoxybenzyl) methylsulfone in the form of a white solid.
  • 1-Benzhydryl-3 - [(methylsulfonyl) (naphth-2-yl) methyl- (RS)] azetidin-3-ol can be obtained in the following manner: by operating according to the procedure of Example 1 starting from 3.5 g of methyl (napht-2-ylmethyl) sulfone and 3.8 g of 1 -benzhydryl azetidin- 3-one, 2.2 g of l-benzhydryl-3 - [(methylsulfonyl) (naphth- 2-yl) methyl- (RS)] azetidin-3-ol in the form of a white solid, melting at 196 ° C.
  • Methyl (napth-2-ylmethyl) sulfone can be prepared in the following manner: by operating according to the procedure of Example 2 from 4.2 g of methyl (napth-2- ylmethyl) sulfide and 13.7 g of oxone R , 3.6 g of methyl (napth-2-ylmethyl) sulfone are obtained in the form of a cream solid.
  • Methyl (napth-2-ylmethyl) sulfide can be prepared in the following manner: by operating according to the procedure of Example 2 from 5 g of 2-bromomethyl naphthalene and 1.8 g of sodium methyl thiolate, 4.2 g of methyl (napth-2-ylmethyl) sulfide are obtained in the form of an oil.
  • Example 4 By operating according to the procedure of Example 4 starting from 4.3 g of 1 -benzhydryl- 3 - [(methylsulfonyl) (napht-1-yl) methyl- (RS)] azetidin-3-ol, from 1 , 1 cm 3 of methanesulfonyl chloride and 4.6 g of 4-dimethylaminopyridine, the residue obtained is purified by chromatography on a column of silica gel (particle size 0.04-0.06 mm, diameter 4 cm, height 30 cm) under a pressure of 0.5 bar of nitrogen with dichloromethane as eluent and collecting fractions of 100 cm 3 .
  • 1-Benzhydryl-3 - [(methylsulfonyl) (naphth-1-yl) methyl- (RS)] azetidin-3-ol can be obtained in the following manner: by operating according to the procedure of Example 1 starting from 4.1 g of methyl (naphth-1-ylmethyl) sulfone and 4.4 g of 1 -benzhydryl azetidin- 3-one, 4.3 g of l-benzhydryl-3 - [(methylsulfonyl) (l- naphthyl) methyl- (RS)] azetidin-3-ol as a solid.
  • Methyl (napht-1-ylmethyl) sulfone can be prepared in the following manner: by operating according to the procedure of Example 2 from 4.3 g of methyl (napht-1 - ylmethyl) sulfide and 13.9 g of oxone R , 4.1 g of methyl (naphth-1-ylmethyl) sulfone are obtained in the form of a white solid.
  • Methyl (naphth-1-ylmethyl) sulfide can be prepared in the following manner: by operating according to the procedure of Example 2, starting with 4 g of 1-chloromethyl naphthalene chloride and 1.8 g of methyl sodium thiolate, 4.5 g of methyl (naphth-1-ylmethyl) sulfide are obtained in the form of an oil.
  • Example 4 By operating according to the procedure of Example 4 starting from 0.6 g of 1-benzhydryl- 3 - [(methylsulfonyl) (3-pyrrolidinophenyl) methyl- (RS)] azetidin-3-ol, from 0.15 cm 3 of methanesulfonyl chloride and 0.6 g of 4-dimethylaminopyridine, the residue obtained is purified by chromatography on a column of silica gel (particle size 0.04-0.06 mm, diameter 2 cm, height 30 cm) under a pressure of 0.5 bar of nitrogen with a mixture of dichloromethane and methanol (98/2 by volume) as eluents and collecting 20 cm 3 fractions.
  • silica gel particle size 0.04-0.06 mm, diameter 2 cm, height 30 cm
  • 1-Benzhydryl-3 - [(methylsulfonyl) (3-pyrrolidinophenyl) methyl- (RS)] azetidin-3-ol can be obtained in the following way: by operating according to the procedure of Example 1 starting from 0 , 77 g of 3-pyrrolidinobenzyl methyl sulfone and 0.76 g of 1 -benzhydryl azetidin-3-one, we obtain 0.6 g of l-benzhydryl-3 - [(methylsulfonyl) (3-pyrrolidinophenyl) methyl- (RS )] azetidin-3-ol as a solid.
  • the methyl (3-pyrrolidinobenzyl) sulfone can be prepared in the following manner: by operating according to the procedure of Example 2, starting from 1 g of methyl (3-pyrrolidinobenzyl) sulfide and 3.3 g of oxone R , 0.8 g of methyl (3-pyrrolidinobenzyl) sulfone is obtained in the form of a solid.
  • Methyl (3-pyrrolidinobenzyl) sulfide can be prepared in the following manner: a mixture of 2 g of (3-iodobenzyl) methylsulfide, 1.3 cm 3 of pyrrolidine, is refluxed under a stream of nitrogen for 3 hours. , 1.1 g of sodium tert-butylate, 0.28 g of chloride l, l -bis (diphenylphosphino) ferrocenyl palladium, 0.63 g of l, l -bis (diphenylphosphino) fer ⁇ ocene and 60 cm 3 of tetrahydrofuran . The reaction medium is cooled to room temperature and filtered through sintered glass.
  • the precipitate is washed with 20 cm 3 of tetrahydrofuran and 10 cm 3 of dichloromethane then the filtrate is concentrated to dryness under reduced pressure (2.7 kPa).
  • the residue is taken up in 30 cm 3 of ethyl acetate and 30 cm 3 of 3N hydrochloric acid.
  • the organic phase is extracted; 4 g of silica are added then the mixture is concentrated to dryness under reduced pressure (2.5 kPa).
  • the powder obtained is eluted on sintered glass containing 20 g of silica with a cyclohexane and ethyl acetate mixture (90/10 by volume).
  • the filtrate is concentrated to dryness under reduced pressure (2.7 kPa).
  • 1.2 g of methyl (3-pyrrolidinobenzyl) sulfide are obtained in the form of an oil.
  • the chloride of l, r-bis (diphenylphosphino) ferrocenyl palladium can be prepared according to Hayashi T. et al., J. Am. Chem. Soc, 106, 158 (1984).
  • a white meringue is obtained which is crystallized from isopropyl ether to obtain 0.85 g of a solid melting at 190 ° C. Recrystallization from 20 cm 3 of ethanol leads to 0.70 g of 1- [bis (4-chlorophenyl) methyl] -3 - [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine melting at 205 ° C.
  • Example 39 To a solution of 6.8 g of bis (4-chlorophenyl) bromomethane in 300 cm 3 of acetonitrile is added 6.75 g of 3 - [(3,5-difluorophenyl) (methylsulfonyl) methyl- hydrochloride (RS)] azetidin-3-ol then 2.97 g of potassium carbonate. The reaction mixture is heated for 1 hour at reflux, cooled to room temperature, filtered and concentrated to dryness under reduced pressure (2.7 kPa).
  • Bis (4-chlorophenyl) bromomethane can be prepared according to the procedure described by BACHMANN W.E., J. Am. Chem. Soc, 2135 (1933).
  • the hydrochloride of 3 - [(3,5-difluorophenyl) (methylsulfonyl) methyl- (RS)] azetidin-3-ol can be obtained in the following way: in a solution of 37 g of 3 - [(3,5- difluorophenyl) (methylsulfonyl) methyl- (RS)] - 1 - (vinyloxycarbonyl) azetidin-3-ol in 160 cm 3 of dioxane 160 cm 3 of a 6.2N solution of hydrochloric acid in dioxane are added. After 16 hours at room temperature, the reaction mixture is concentrated to dryness under reduced pressure (2.7 kPa).
  • reaction mixture is concentrated to dryness under reduced pressure (2.7 kPa).
  • the residue obtained is chromatographed on a column of silica gel (particle size 0.04-0.06 mm, diameter 11 cm, height 32 cm), under a pressure of 0.5 bar of argon with a mixture of acetate. ethyl and cyclohexane (3/7 by volume) as eluents and collecting fractions of 1000 cm 3 .
  • Fractions 8 to 18 are combined and then concentrated to dryness under reduced pressure (2.7 kPa).
  • L- [bis (4-chlorophenyl) methyl] azetidin-3-one can be prepared according to the following procedure: to a solution of 5.0 cm 3 of oxalyl chloride in 73 cm 3 of dichloromethane cooled to -78 ° C, a solution of 8.1 cm 3 of dimethyl sulfoxide in 17.6 cm 3 of dichloromethane is added. After 0.5 hours at -78 ° C., a solution of 16.0 g of 1- [bis (4-chlorophenyl) methyl] azetidin-3-ol dissolved in 50 cm 3 of dichloromethane.
  • 1- [bis (4-chlorophenyl) methyl] azetidin-3-ol can be prepared according to the procedure described by KATRITZKY AR et al., J. Heterocycl. Chem., (1994), 271 starting from 35.5 g of [bis (4-chlorophenyl) methyl] amine hydrochloride and 11.0 cm 3 of epichlorohydrin. 9.0 g of 1- [bis (4-chlorophenyl) methyl] azetidin-3-ol are isolated.
  • Example 38 By operating according to the procedure of Example 38 (method 1), starting from 0.72 g of 1 - [bis (4-methoxyphenyl) methyl] -3 - [(3,5-difluorophenyl) (methylsulfonyl) methyl - (RS)] azetidin-3-ol and after chromatography on a column of silica gel (particle size 0.04-0.06 mm, diameter 4.0 cm, height 16.5 cm), under a pressure of 0.5 bar of argon with a mixture of ethyl acetate and cyclohexane (2/8 by volume) as eluent and collecting 40 cm 3 fractions, 0.10 g of a white meringue is obtained.
  • Bis (4-methoxyphenyl) bromomethane can be prepared according to the procedure described by BACHMANN W.E., J. Am. Chem. Soc, 2135 (1933).
  • L- [bis (4-methylphenyl) methyl] -3 - [(3,5-difluorophenyl) (methylsulfonyl) methyl- (RS)] azetidin-3-ol can be obtained as follows: by operating as in Example 39 from 0.7 g of bis (4-methylphenyl) bromomethane and 0.8 g of 3 - [(3,5-difluorophenyl) (methylsulfonyl) methyl- (RS)] azetidin-3- hydrochloride ol and after chromatography on a column of silica gel (particle size 0.04-0.06 mm, diameter 4.0 cm, height 19 cm), under a pressure of 0.5 bar of argon with a mixture of ethyl acetate and cyclohexane (2/8 by volume) as eluent and collecting 40 cm 3 fractions, fractions 35 to 40 are combined and then concentrated to dryness under reduced pressure (2.7 kPa).
  • Bis (4-methylphenyl) bromomethane can be prepared according to the procedure described by BACHMANN W.E., J. Am. Chem. Soc, 2135 (1933).
  • the mixture of diastereoisomers 3 - [(3,5-difluorophenyl) (methylsulfonyl) methyl- (RS)] - l - [(4-methoxyphenyl) (phenyl) methyl- (RS)] azetidin-3-ol can be obtained from as follows: by operating according to Example 39 from 2.52 g (RS) -bromo (4-methoxyphenyl) (phenyl) methane and 2.85 g of hydrochloride of 3 - [(3,5-difluorophen- nyl) (methylsulfonyl) methyl- (RS)] azetidin-3-ol and after chromatography on a column of silica gel (particle size 0.04-0.06 mm, diameter 5.6 cm, height 19 cm), under pressure 0.5 bar of argon with a mixture of ethyl acetate and cyclohexane (25/75 by volume)
  • L- [bis (4-trifluoromethoxyphenyl) methyl] -3 - [(3,5-difluorophenyl) (methylsulfonyl) methyl- (RS)] azetidin-3-ol can be obtained in the following way: by operating as in Example 39 from 1.59 g of bis (4-trifluoromethoxyphenyl) bromomethane and 1.2 g of 3 - [(3,5-difluorophenyl) (methylsulfonyl) methyl- (RS) hydrochloride ] azetidin-3-ol and after chromatography on a column of silica gel (particle size 0.04-0.06 mm, diameter 4.8 cm, height 17 cm), under a pressure of 0.5 bar of argon with a mixture of ethyl acetate and cyclohexane (25/75 by volume) as eluent and collecting 50 cm 3 fractions, fractions 15 to 23 are combined and then concentrated
  • Bis (4-trifluoromethoxyphenyl) bromomethane can be prepared according to the procedure described by BACHMANN WE, J. Am. Chem. Soc, 2135 (1933), starting with 1.39 g of bis (4-trifluoromethoxyphenyl) methanol, 3 cm 3 of hydrobromic acid at 33% in acetic acid and 0.6 cm 3 of bromide acetyl. 1.59 g of bis (4-trifluoromethoxyphenyl) bromomethane are obtained in the form of a brown oil.
  • Bis (4-trifluoromethylphenyl) bromomethane can be prepared according to the procedure described by BACHMANN WE, J. Am. Chem. Soc, 2135 (1933), starting from 2.5 g of bis (4-trifluoromethylphenyl) methanol, 6 cm 3 of hydrobromic acid at 33% in acetic acid and 1.2 cm 3 of acetyl bromide. 2.9 g of bis (4-trifluoromethylphenyl) bromomethane are obtained in the form of a brown oil.
  • 3-acetoxy-1- [bis (4-chlorophenyl) methyl] -3 - ⁇ [3,5-bis (trifluoromethyl) phenyl] (methylsulfonyl) methyl- (RS) ⁇ azetidine can be obtained as follows: by operating as in Example 40, starting with 2.0 g of [3,5-bis (trifluoromethyl) benzyl] methylsulfone, 4.1 cm 3 of a 1.6N solution of nbutyllithium in hexane, 2, 0 g of 1- [bis (4-chlorophenyl) methyl] azetidin-3-one and 0.77 cm 3 of acetyl chloride in 20 cm 3 of anhydrous diisopropyl oxide, after chromatography on a silica gel column, (particle size 0.04-0.06 mm, diameter 5.6 cm, height 16 cm), under a pressure of 0.5 bar of argon with a mixture of ethyl acetate and cycl
  • the [3,5-bis (trifluoromethyl) benzyl] methylsulfone is prepared in the following manner: by operating according to example 10 from 1.8 g of 3,5-bis (trifluoromethyl) benzyl chloride and 1.22 g of sodium methanesulfinate, 1.86 g of [3,5-bis (trifluoromethyl) benzyl] methylsulfone are obtained in the form of a white solid.
  • (RS) -bromo (4-chlorophenyl) (2,4-dichlorophenyl) methane can be prepared according to the procedure described by BACHMANN WE, J. Am. Chem. Soc, 2135 (1933) starting from 4.05 g of (RS) - (4-chlorophenyl) (2,4-dichlorophenyl) methanol, 10 cm 3 of hydrobromic acid at 33% in acetic acid and 2, 1 cm 3 of acetyl bromide. 4.6 g of (RS) -bromo (4-chlorophenyl) (2,4-dichlorophenyl) methane are obtained in the form of a greenish oil.
  • L - ⁇ (4-chlorophenyl) [4- (1,3-dioxolan-2-yl) phenyl] methyl- (RS) ⁇ - 3 - [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine can be prepared according to the following method: to a solution of 34.45 g of the mixture of the two diastereoisomers 3-aceto-toxy- 1 - ⁇ (4-chlorophenyl) [4- (1, 3-dioxolan-2-yl) phenyl ] methyl- (RS) ⁇ - 3 - [(3,5-difluorophenyl) (methylsulfonyl) methyl- (RS)] azetidine in 400 cm 3 of tetrahydrofuran under argon at 0 ° C., added dropwise 13, 0 cm 3 of l, 8-diazabicyclo [5-4
  • 1 - ⁇ (4-chlorophenyl) [4- (1, 3-dioxolan-2-yl) phenyl] methyl- (RS) ⁇ azetidin-3-one can be prepared as follows: to a solution of 28, 32 g of l - ⁇ (4-chlorophenyl) [4- (1,3-dioxolan-2-yl) phenyl] methyl- (RS) ⁇ azetidin-3-ol in 200 cm 3 of dimethyl sulfoxide, room temperature 46 cm 3 of triethylamine, then a solution of 34 g of the sulfur trioxide-pyridine complex in 100 cm 3 of dimethyl sulfoxide is added dropwise.
  • the reaction mixture is poured onto ice, extracted with ethyl acetate, washed with 3 times 400 cm 3 of water and then with 400 cm 3 of a saturated solution of sodium chloride, dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa).
  • the residue obtained is chromatographed on a silica gel column (particle size 0.04-0.06 mm, diameter 9.2 cm, height 21 cm), under a pressure of 0.5 bar of argon with a mixture of acetate ethyl and cyclohexane (20/80 by volume) as eluent and collecting fractions of 250 cm 3 .
  • reaction mixture is diluted with dichloromethane, washed twice with 80 cm 3 of water and then 80 cm 3 of a saturated solution of sodium chloride, dried over magnesium sulphate, filtered and concentrated to dry under reduced pressure (2.7 kPa).
  • the residue obtained is chromatographed on a silica gel column (particle size 0.04-0.06 mm, diameter 4.1 cm, height 13 cm), under a pressure of 0.5 bar of argon with a dichloromethane mixture. / acetonitrile / methanol (98/1/1 by volume) as eluent and collecting 15 cm 3 fractions. Fractions 13 to 15 are combined and then concentrated to dryness under reduced pressure (2.7 kPa).
  • (RS) -1 - ⁇ (4-carboxyphenyl) (4-chlorophenyl) methyl] -3 - [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine can be prepared as follows: To a solution of 0.50 g of (RS) -l - ⁇ (4-chlorophenyl) (4-formylphenyl) methyl ⁇ -3 - [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine in 10 cm 3 of acetone to 0 ° C, 1.0 cm 3 of Jones' reagent is added.
  • the reaction mixture is poured into distilled water, the product is extracted with 50 cm 3 of ethyl acetate, the organic phase is washed twice with 50 cm 3 of water and then 50 cm 3 d '' a saturated solution of sodium chloride, dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa).
  • the solid obtained is crystallized from an ethyl acetate-cyclohexane mixture, filtered and dried.
  • Example 52 The operation is carried out according to Example 52, starting from 1 g of (RS) -1 - ⁇ (4-carboxyphenyl) (4-chlorophenyl) methyl] -3 - [(3,5-difluorophenyl) (methylsulfonyl) methylene ] azetidine, 0.38 g of 1,3-dimethylaminopropyl 3-ethyl carbodumide hydrochloride, 22 mg of hydroxybenzotriazole hydrate, 40 cm 3 of dichloromethane and 0.24 cm 3 of a 7N solution of ammonia in methanol and by chromatography on a column of silica gel (particle size 0.04-0.06 mm, diameter 4.1 cm, height 15 cm), under a pressure of 0.5 bar of argon with a mixture of ethyl acetate and cyclohexane (60/40 by volume) as eluent and collecting fractions of 35 cm 3 .
  • Example 4 The procedure of Example 4 is used starting from 1.7 g of 1 - [bis (4-chlorophenyl) methyl] -3 - [(3,5-dichlorophenyl) (methylsulfonyl) methyl- (RS )] azetidin-3-ol, 0.35 cm 3 of methanesulfonyl chloride and 1.5 g of 4-dimethylaminopyridine.
  • the residue obtained is purified by chromatography on a column of silica gel (particle size 0.04-0.06 mm, diameter 3 cm, height 35 cm) under a pressure of 0.5 bar of nitrogen with a mixture of dichloromethane and ethanol ( 99.5 / 0.5 by volume) as eluent and collecting 100 cm 3 fractions. Fractions 7 to 10 are combined and concentrated to dryness under reduced pressure (2.7 kPa). The solid is crystallized from 15 cm 3 of ethyl ether. 0.2 g of 1- [bis (4-chlorophenyl) methyl] -3- [(3,5-dichlorophenyl) (methylsulfonyl) methylene] azetidine is obtained, melting at 200 ° C.
  • L- [bis (4-chlorophenyl) methyl] -3 - [(3,5-dichlorophenyl) (methylsulfonyl) methyl- (RS)] azetidin-3-ol can be obtained in the following way: by operating according to the procedure of Example 39 from 4 g of bis (4-chlorophenyl) bromomethane and 3 g of 3 - [(3,5-dichlorophenyl) (methylsulfonyl) methyl- (RS)] azetidin-3-ol hydrochloride, the residue obtained is purified by chromatography on a column of silica gel (particle size 0.04-0.06 mm, diameter 3 cm, height 40 cm) under a pressure of 0.5 bar of nitrogen with dichloromethane then a dichloromethane mixture and ethanol (99/1 by volume) as eluent and collecting fractions of 100 cm 3 .
  • Bis (4-chlorophenyl) bromomethane can be prepared according to the procedure described by BACHMANN W.E., J. Am. Chem. Soc, 2135 (1933).
  • the hydrochloride of 3 - [(3,5-dichlorophenyl) (methylsulfonyl) methyl- (RS)] azetidin-3-ol can be obtained in the following way: by operating according to the procedure of Example 39 starting from 5 , 6 g of 3 - [(3,5-dichlorophenyl) (methylsulfonyl) methyl- (RS)] - l- (vinyloxycarbonyl) azetidin-3-ol and 56 cm 3 of a solution of 6,2N hydrochloric dioxane in 56 cm 3 of dioxane, 5.1 g of 3 - [(3,5-dichlorophenyl) (methylsulfonyl) methyl- (RS)] azetidin-3-ol hydrochloride are obtained in the form of a meringue.
  • Example 4 By operating according to the procedure of Example 4 starting from 0.5 g of 1 -benzhydryl- 3 - [(3-dimethylaminophenyl) (methylsulfonyl) methyl- (RS)] azetidin-3-ol, from 0.1 cm 3 of methanesulfonyl chloride and 0.5 g of 4-dimethylaminopyridine, the residue obtained is purified by chromatography on a column of silica gel (particle size 0.04-0.06 mm, diameter 2 cm, height 30 cm) under a pressure of 0.5 bar of nitrogen with a mixture of dichloromethane and ethanol (98/2 by volume) as eluent and collecting 20 cm 3 fractions.
  • 1-Benzhydryl-3 - [(3-dimethylaminophenyl) (methylsulfonyl) methyl- (RS)] azetidin-3-ol can be obtained in the following way: by operating according to the procedure of Example 1 starting from 0 , 4 g of (3-d_methylaminobenzyl) methylsulfone, 0.4 g of 1-benzhydryl azetidin-3-one and 1.2 cm 3 of a 1.6M solution of nbutyllithium in hexane, 0.5 is obtained g of 1-benzhydryl-3 - [(3-dimethylaminophenyl) (methylsulfonyl) methyl- (RS)] azetidin-3-ol in the form of a solid melting at 185 ° C.
  • (3-Dimethylaminobenzyl) methylsulfone can be prepared in the following manner: by operating according to the procedure of Example 2 from 1.4 g of (3-dimethylaminobenzyl) methylsulfide and 5.1 g of oxone R , 1.1 g of (3-dimethylaminobenzyl) methylsulfone are obtained in the form of a white solid, melting at 195 ° C.
  • (3-Dimethylaminobenzyl) methylsulfide can be prepared in the following manner: by operating according to the procedure of Example 37, starting with 4 g of (3-iodobenzyl) methylsulfide, 1.4 g of dimethylamine in solution in 5 cm 3 of tetrahydrofuran, 2.9 g of sodium tert-butoxide, 0.56 g of l, l -bis (diphenylphosphino) fer ⁇ ocenyl palladium chloride and 1.3 g of l, l-l (l -bis (diphenylphosphino) ferrocene in 35 cm 3 of tetrahydrofuran, 0.9 g of (3-dimethylaminobenzyl) methylsulfide is obtained in the form of an oil.
  • Example 4 Operating according to the procedure of Example 4, starting with 1.3 g of 1-benzhydryl- 3 - [(3-methylsulfanylphenyl) (methylsulfonyl) methyl- (RS)] azetidin-3-ol, of 0.3 cm 3 of methanesulfonyl chloride and 1.4 g of 4-dimethylaminopyridine, the residue obtained is purified by chromatography on silica gel color (particle size 0.04-0.06 mm, diameter 2 cm, height 30 cm) under a pressure of 0.5 bar of nitrogen with a mixture of dichloromethane and ethanol (98/2 by volume) as eluent and collecting 20 cm 3 fractions.
  • L-Benzhydryl-3 - [(3-methylsulfanylphenyl) (methylsulfonyl) methyl- (RS)] azetidin-3-ol can be obtained in the following way: by operating according to the procedure of Example 1 starting from 1 , 1 g of methyl (3-methylsulfanylbenzyl) sulfone, of 1.2 g of 1-benzhydryl azetidin-3-one, we obtain 1.3 g of l-benzhydryl-3 - [(3-methylsulfanyl-phenyl) (methylsulfonyl ) methyl- (RS)] azetidin-3-ol as a solid.
  • Methyl (3-methylsulfanylbenzyl) sulfone can be prepared in the following manner: the mixture is heated to a temperature close to 100 ° C., under a stream of argon, for 1 hour a mixture of 5g of (3-iodobenzyl) methylsulfone and 1g of tetrakistriphenylphosphine palladium in 250 cm 3 of dimethylsulfoxide. 2.5 g of sodium methylthiolate are added and then the heating to 100 ° C. is maintained for 18 hours. The reaction medium is cooled to room temperature, taken up in 700 cm 3 of ethyl acetate and 500 cm 3 of water.
  • the organic phase is decanted, washed with 10 times 500 cm 3 of water, 500 cm 3 of a saturated aqueous solution of sodium chloride, filtered through sintered glass and concentrated to dryness under reduced pressure (2.7 kPa).
  • the residue obtained is purified by chromatography on a column of silica gel (particle size 0.04-0.06 mm, diameter 3 cm, height 30 cm) under a pressure of 0.5 bar of nitrogen with a cyclohexane mixture and ethyl acetate (70/30 then 60/40 then 50/50 by volume) as eluent and collecting 30 cm 3 fractions.
  • Fractions 26 to 30 are combined and concentrated to dryness under reduced pressure (2.7 kPa).
  • 1.2 g of methyl (3-methylsulfanylbenzyl) methylsulfone are obtained in the form of an oil.
  • the organic phase is decanted, extracted, dried over anhydrous magnesium sulfate and concentrated to dryness under reduced pressure (2.7 kPa).
  • the residue obtained is purified by chromatography on a column of silica gel (particle size 0.04-0.06 mm, diameter 2 cm, height 30 cm) under a pressure of 0.5 bar of nitrogen with a mixture of dichloromethane and ethanol ( 95/5 by volume) as eluent and collecting 60 cm 3 fractions. Fractions 4 to 6 are combined and concentrated to dryness under reduced pressure (2.7 kPa).
  • 1 -benzhydryl-3 - ⁇ [3 - (tert-butyldimethylsilyloxymethyl) phenyl] (methylsulfonyl) methylene ⁇ azetidine can be prepared as follows: by operating according to the procedure of Example 4 starting from 1, 6 g of 1-benzhydryl-3 - ⁇ [3- (tert-butyldimethylsilyloxymethyl) phenyl] (methylsulfonyl) methyl- (RS)] azetidin-3-ol, 0.3 cm 3 of methanesulfonyl chloride and 1.4 g of 4-dimethylaminopyridine, the residue obtained is purified by chromatography on a column of silica gel (particle size 0.04-0.06 mm, diameter 3 cm, height 30 cm) under a pressure of 0.5 bar of nitrogen with dichloromethane as eluent and collecting 60 cm 3 fractions.
  • 1 -benzhydry 1-3 - ⁇ [3 - (tert-butyldimethylsilyloxymethyl) phenyl] (methylsulfonyl) methyl- (RS)] azetidin-3-ol can be obtained in the following way: by operating according to the operating procedure of example 1 from 2 g of [3- (tert-butyldimethylsilyloxy-methyl) benzyl] methylsulfone and 1.5 g of 1 -benzhydryl azetidin-3-one, 1.6 g of l-benzhydryl-3- ⁇ [3- (tert-butyldimethylsilyloxymethyl) phenyl] (methylsulfonyl) methyl- (RS)] azetidin-3-ol as a white solid, melting at 175 ° C.
  • the [3- (tert-butyldimethylsilyloxymethyl) benzyl] methylsulfone can be prepared in the following manner: a mixture of 13.4 g of (3-hydroxymethylbenzyl) methylsulfone, 11 g d, is stirred for 18 hours at a temperature close to 20 ° C. 'imidazole and 12 g of tert-butyldimethylsilane chloride. The solution is concentrated to dryness under reduced pressure (2.7 kPa).
  • the residue obtained is purified by chromatography on a column of silica gel (particle size 0.04-0.06 mm, diameter 5 cm, height 50 cm) under a pressure of 0.5 bar of nitrogen with dichloromethane as eluent and collecting fractions of 100 cm 3 .
  • Fractions 7 to 14 are combined and concentrated to dryness under near- reduced pressure (2.7 kPa). 5.7 g of [3- (tert-butyldimethylsilyloxymethyl) benzyl] methylsulfone are obtained in the form of a white solid, melting at 80 ° C.
  • the (3-hydroxymethylbenzyl) methylsulfone can be prepared in the following manner: a mixture of 26 g of 3- (methylsulfonylmethyl) benzoic acid and 4.6 g of hydride is stirred for 18 hours at a temperature close to 20 ° C. lithium and aluminum in 600 cm 3 of tetrahydrofuran. The solution is cooled to 0 ° C. then 15 cm 3 of ethyl acetate, 5 cm 3 of water, 5 cm 3 of a 15% aqueous solution of sodium hydroxide and finally 30 cm 3 of water. The mixture is filtered through celite, the filtrate taken up in 600 cm 3 of ethyl acetate.
  • 3- (methylsulfonylmethyl) benzoic acid can be prepared in the following manner: by operating according to the procedure of Example 10 from 23.3 g of 3-chloromethylbenzoic acid and 23.3 g of sodium methanesulfinate , 26 g of 3- (methylsulfonylmethyl) benzoic acid are obtained in the form of a white solid, melting at 210 ° C.
  • the residue obtained is purified by chromatography on a column of silica gel (particle size 0.04-0.06 mm, diameter 2 cm, height 28 cm) under a pressure of 0.5 bar of nitrogen with a cyclohexane mixture and ethyl acetate (90/10 by volume) as eluent and collecting 50 cm 3 fractions.
  • Fractions 8 to 14 are combined and concentrated to dryness under reduced pressure (2.7 kPa).
  • 0.3 g of l-benzhydryl-3 - ⁇ [3- (methylsulfanylmethyl) phenyl] (methylsulfonyl) methylene ⁇ azetidine is obtained in the form of a white solid, melting at 150 ° C.
  • 1-Benzhydryl-3 - [(3-bromomethylphenyl) (methylsulfonyl) methylene] azetidine can be prepared as follows: to a mixture of 1 g of l-benzhydryl-3 - [(3-hydroxymethylphenyl) (methylsulfonyl) methylene ] azetidine in 10 cm 3 of dichloromethane, 0.23 cm 3 of phosphorus tribromide and then a drop of pyridine are added at a temperature close to 20 ° C. Stirring is continued for 18 hours at the same temperature. The reaction medium is taken up in 20 cm 3 of water and 10 cm 3 of an aqueous solution saturated with sodium chloride.
  • Example 4 By operating according to the procedure of Example 4 starting from 6.6 g of 1-benzhydryl- 3 - [(methylsulfonyl) (quinol-8-yl) methyl- (RS)] azetidin-3-ol, from 1 , 7 cm 3 of methanesulfonyl chloride and 5.2 g of 4-dimethylaminopyridine, the residue obtained is purified by chromatography on a column of silica gel (particle size 0.04-0.06 mm, diameter 6.5 cm, height 35 cm) under a pressure of 0.5 bar of nitrogen with a mixture of dichloromethane and methanol (95/5 by volume) as eluent and collecting 40 cm 3 fractions.
  • 1-Benzhydryl-3 - [(methylsulfonyl) (quinol-8-yl) methyl- (RS)] azetidin-3-ol can be obtained in the following way: by operating according to the procedure of Example 1 starting from 5.5 g of methyl (quinol-8-ylmethyl) sulfone, 5.9 g of 1 -benzhydryl azetidin-3-one and 18.8 cm 3 of a 1.6 M solution of nbutyllithium in 1 hexane, 6.6 g of 1-benzhydryl-3 - [(methylsulfonyl) (quinol-8-yl) methyl- (RS)] azetidin-3-ol are obtained in the form of a beige solid.
  • Methyl (quinol-8-ylmethyl) sulfone can be prepared in the following manner: by operating according to the procedure of Example 10 from 4.5 g of 8-chloromethylquinoline and 4.4 g of methanesulfinate sodium, 5.7 g of methyl (quinol-8-ylmethyl) sulfone are obtained in the form of a beige solid.
  • 8-chloromethylquinoline can be prepared in the following manner: to a mixture of 7.1 g of 8-methylquinoline in 250 cm 3 of carbon tetrachloride, 6.7 g of N are added at a temperature close to 20 ° C. -chlorosuccinimide then 250 mg of benzoyl peroxide. The reaction medium is heated at reflux of the solvent for 36 hours and then cooled to 20 ° C. The mixture is filtered on sintered glass, the filtrate is concentrated to dryness under reduced pressure (2.7 kPa).
  • the residue obtained is purified by chromatography on a column of silica gel (particle size 0.04-0.06 mm, diameter 5.5 cm, height 32 cm) under a pressure of 0.5 bar of nitrogen with dichloromethane as eluent and collecting 40 cm 3 fractions. Fractions 21 to 40 are combined and concentrated to dryness under reduced pressure (2.7 kPa). 4.5 g of 8-chloroméfhylquinoline are obtained in the form of a brown oil used in the crude state in the subsequent syntheses.
  • Example 4 By operating according to the procedure of Example 4 starting from 6.2 g of 1- [bis (4-chlorophenyl) methyl] -3 - [(3-cyanophenyl) (methylsulfonyl) methyl- (RS)] azetidin-3-ol, 1.4 cm 3 of methanesulfonyl chloride and 6.1 g of 4-dimethylaminopyridine, the residue obtained is purified by chromatography on a column of silica gel (particle size 0.04-0.06 mm, diameter 4 cm, height 60 cm) under a pressure of 0.5 bar of nitrogen with dichloromethane as eluent and collecting fractions of 100 cm 3 .
  • (RS)] azetidin-3-ol can be obtained in the following manner: by operating according to the procedure of Example 1 from 5.5 g of (3-cyanophenyl) methylsulfone, from 6.1 g of l - [bis (4-chlorophenyl) methyl] azetidin-3-one and 13.8 cm 3 of a 1.6 M solution of nbutyllithium in hexane, 6.3 g of l- [bis (4- chlorophenyl) methyl] -3 - [(3-cyanophenyl) (methylsulfonyl) methyl- (RS)] azetidin-3-ol in the form of a meringue.
  • the solid obtained is purified by chromatography on a color of silica gel (particle size 0.04-0.06 mm, diameter 25 cm, height 40 cm) under a pressure of 0.5 bar of nitrogen with dichloromethane and then a dichloromethane mixture. and ethanol (99.5 / 0.5 by volume) as eluent and collecting 30 cm 3 fractions. Fractions 35 to 46 are combined and concentrated to dryness under reduced pressure (2.7 kPa). The solid obtained is crystallized from 15 cm 3 of ethyl ether.
  • 1 -benzhydryl-3 - ⁇ [3 - (N-tert-butyloxycarbonyl-N-methylamino) phenyl] (methylsulfonyl) methyl- (RS) ⁇ azetidin-3-ol can be obtained in the following way: operating according to the procedure of Example 1 from 1.6 g of [3- (N-tert-butyloxycarbonyl-N-methylamino) benzyl] methylsulfone, from 1.3 g of 1 -benzhydryl azetidin-3-one and 3.8 cm 3 of a 1.6 M solution of nbutyllithium in hexane, 0.8 g l-benzhydryl-3 - ⁇ [3- (N-tert-butyloxycarbonyl-N-methyl-lamino) is obtained phenyl] (methylsulfonyl) methyl- (RS) ⁇ azetidin-3-ol as a white solid
  • [3- (N-tert-butyloxycarbonyl-N-methylamino) benzyl] methylsulfone can be prepared as follows: to a solution cooled to 0 ° C of methyl (3-methylaminobenzyl) sulfone in 30 cm 3 of dioxane 2.5 g of ditertiobutyldicarbonate in 40 cm 3 of dioxane are added. Stirring is continued for 18 hours at room temperature. The reaction medium is taken up in 75 cm 3 of dichloromethane; the organic phase is washed with 75 cm 3 of water and then with 75 cm 3 of an aqueous solution saturated with sodium chloride.
  • the organic phase is decanted, extracted, dried over anhydrous sodium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa).
  • the residue obtained is purified by chromatography on a column of silica gel (particle size 0.04-0.06 mm, diameter 2 cm, height 35 cm) under a pressure of 0.5 bar of nitrogen with a cyclohexane and acetate mixture. ethyl (50/50 by volume) as eluent by collecting fractions of 20 cm 3 . Fractions 5 to 10 are combined and concentrated to dryness under reduced pressure (2.7 kPa). 1.8 g of [3- (N-tert-butyloxycarbonyl-N-methylamino) benzyl] methylsulfone are obtained in the form of a colorless oil.
  • the mixture is filtered on sintered glass, the precipitate is washed with 3 times 50 cm 3 of diisopropyl ether and then dried.
  • the filtrate is concentrated by half in volume (2.7 kPa), the precipitate obtained is filtered on sintered glass and washed with 3 times 30 cm 3 of diisopropyl ether and then dried.
  • the two precipitates are combined and dissolved in 375 cm 3 of tetrahydrofuran.
  • the solution is cooled to 0 ° C; 100 cm 3 of a 2 M solution of borane dimethylsulfide in tetrahydrofuran are added and the mixture is then refluxed for 3 hours.
  • the mixture is cooled to 5 ° C. and then 60 cm 3 of methanol are added over 20 minutes.
  • the aqueous phase is made alkaline with 120 cm 3 of 3 N sodium hydroxide solution, then with an aqueous solution of sodium bicarbonate.
  • the organic phase is extracted with 2 times 75 cm 3 of ethyl acetate, dried over anhydrous magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa). 9 g of methyl (3-methylaminobenzyl) sulfone are obtained in the form of a pink solid.
  • the reaction medium is basified with an aqueous ammonia solution and then with an aqueous sodium bicarbonate solution.
  • the organic phase is extracted with 3 times 250 cm 3 of ethyl acetate, dried over magnesium sulfate, filtered through sintered glass and concentrated to dryness under reduced pressure (2.7 kPa). 14.9 g of (3-aminobenzyl) methylsulfone are obtained in the form of a beige solid used in the crude state in the subsequent syntheses.
  • Example 64 A mixture of 0.3 g of 1 -benzhydry 1-3- ⁇ [3- (N-tert-butyloxycarbonyl-N-methylamino) phenyl] (methylsulfonyl) methylene ⁇ azetidine, 4 cm 3 d, is stirred for 18 hours at room temperature. '' a 4.7 N solution of hydrochloric dioxane and 4 cm 3 of dioxane. The reaction medium is concentrated to dryness under reduced pressure (2.7 kPa). The residue is taken up in 100 cm 3 of water and 20 cm 3 of diethyl ether. The aqueous phase is basified with 30 cm 3 of an aqueous solution of sodium bicarbonate.
  • (RS)] azetidin-3-ol can be obtained in the following manner: by operating according to the procedure of Example 1 from 6.6 g of (3-methoxybenzyl) methylsulfone, 10 g of l- [bis (4-chlorophenyl) methyl] azetidin-3-one and 23 cm 3 of a 1.6 N solution of nbutyllithium in hexane, 11.4 g of l- [bis ( 4-chlorophenyl) methyl] -3- [(3-methoxyphenyl) (methylsulfonyl) methyl- (RS)] azetidin-3-ol as a white solid, melting at 130 ° C.
  • L- [bis (4-chlorophenyl) methyl] -3 - [(methylsulfonyl) (3-pyrrolidinylphenyl) methyl- (RS)] azetidin-3-ol can be obtained in the following manner: by operating according to the operating procedure Example 1 from 0.5 g of methyl (3-pyrrolidinylbenzyl) sulfone, 0.6 g of l- [bis (4-chlorophenyl) methyl] azetidin-3-one and 1.4 cm 3 of a 1.6 N solution of n butyllithium in hexane, 0.6 g of l- [bis (4-chlorophenyl) methyl] -3- [(methylsulfonyl) (3-pyrrolidinylphenyl) methyl- (RS)] is obtained azetidin-3-ol as a cream solid.
  • Example 58 By operating according to the procedure of Example 58 from 5.1 g of 1- [bis (4-chlorophenyl) methyl] -3- ⁇ [3- (tert-butyldimethylsilyloxymethyl) phenyl] (methylsulfonyl) methylene ⁇ azetidine and 17 cm 3 of a 1M solution of tetrabutylammmonium fluoride in tetrahydrofuran, the residue obtained is purified by chromatography on a column of silica gel (particle size 0.04-0.06 mm, diameter 2 cm, height 30 cm ) under a pressure of 0.5 bar of nitrogen with a mixture of dichloromethane and ethanol (97/3 by volume) as eluent and collecting fractions of 100 cm 3 .
  • a mixture of 0.45 g of 1- [bis (4-chlorophenyl) methyl] -3 - ⁇ (methylsulfonyl) [3- (pentafluorophenoxycarbonyl) phenyl] methylene ⁇ azetidine is stirred for 18 hours at room temperature. 3 of 1 -aminopiperidine in 4 cm 3 of dimethylformamide. The mixture is taken up in 30 cm 3 of ethyl acetate. The organic phase is washed with 3 times 50 cm 3 of water, dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa).
  • L- [bis (4-chlorophenyl) methyl] -3 - [(3-carboxyphenyl) (methylsulfonyl) methylene] azetidine can be prepared as follows: to a mixture of 0.5 g of l- [bis (4 -chlorophenyl) methyl] -3 - [(3-hydroxymethylphenyl) (methylsulfonyl) methylene] azetidine in 9 cm 3 of acetone, cooled to 5 ° C., 2 cm 3 of Jones reagent are added. Stirring is continued for 2 hours at this temperature, then 50 cm 3 of a mixture of water and ice and 50 cm 3 of ethyl acetate are added.
  • the organic phase is decanted, washed with 50 cm 3 of a saturated aqueous solution of sodium chloride, dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa).
  • the residue obtained is purified by chromatography on a column of silica gel (particle size 0.04-0.06 mm, diameter 3 cm, height 25 cm) under a pressure of 0.5 bar of nitrogen with a mixture of dichloromethane and ethanol as eluent and collecting 60 cm 3 fractions. Fractions 12 to 14 are combined, concentrated to dryness under reduced pressure (2.7 kPa).
  • the solid obtained is crystallized from 10 cm 3 of ethyl ether.
  • Fractions 12 to 17 are combined, concentrated to dryness under reduced pressure (2.7 kPa).
  • the residue obtained is purified again by chromatography on silica gel color (grain size 0.04-0.06 mm, diameter 2 cm, height 20 cm) under a pressure of 0.5 bar of nitrogen with dichloromethane as eluent and collecting 30 cm 3 fractions.
  • Fractions 15 to 28 are combined, concentrated to dryness under reduced pressure (2.7 kPa). 0.25 g of l- [bis (4-chlorophenyl) methyl] -3 - [(methylsulfonyl) (3-trifluoromethylsulfanylphenyl) methylene] azetidine is obtained, melting at 70 ° C.
  • L- [bis (4-chlorophenyl) methyl] -3 - [(methylsulfonyl) (3-trifluoromethylsulfanylphenyl) methyl- (RS)] azetidin-3-ol can be obtained in the following way: by operating according to the procedure of Example 1 from 2 g of methyl (3-trifluoromethylsulfanylbenzyl) sulfone, from 2.3 g of 1- [bis (4-chlorophenyl) methyl] azetidin-3-one and 5.5 cm 3 of a 1.6M solution of n butyllithium in hexane, 0.9 g of l-benzhydryl-3 - [(methylsulfonyl) (3-trifluoromethylsul- fanylphenyl) methyl- (RS)] is obtained azetidino-3-ol as a white solid.
  • the methyl (3-trifluoromethylsulfanylbenzyl) sulfone can be prepared in the following manner: by operating according to the procedure of Example 10 from 5 g of 3-trifluoromethylsulfanylbenzyl chloride and 3.2 g of sodium methanesulfinate, 5.2 g of methyl (3-trifluoromethylsulfanylbenzyl) sulfone in the form of a white solid, melting at 125 ° C.
  • Example 38 By operating as in Example 38 (method 1), from 0.72 g of l- [bis (4-fluorophenyl) methyl] -3 - [(3,5-difluorophenyl) (methylsulfonyl) methyl- (RS)] azetidin-3-ol, 0.18 cm 3 of methanesulfonyl chloride and 0.66 g of 4-dimehylaminopyridine, obtained after chromatography on a column of silica gel (particle size 0.04-0.06 mm , diameter 2.5 cm, height 15 cm), under a pressure of 1 bar of argon with a mixture of ethyl acetate and cyclohexane (15/85 by volume) as eluent and collecting fractions of 25 cm 3 , 0.42 g of 1- [bis (4-fluorophenyl) methyl] -3 - [(3,5- difluorophenyl) (methylsulfonyl) methylene] a
  • L- [bis (4-fluorophenyl) methyl] -3 - [(3,5-difluorophenyl) (methylsulfonyl) methyl- (RS)] azetidin-3-ol can be obtained in the following way: the procedure is as in Example 39 from 2.25 g of bis (4-fluorophenyl) bromomethane, 1.1 g of potassium carbonate, and 2.5 g of 3 - [(3,5-difluorophenyl) hydrochloride ( methylsulfonyl) methyl- (RS)] azetidin-3-ol.
  • fractions 23 to 39 are combined and then concentrated to dry under reduced pressure (2.7 kPa). 0.72 g of l- [bis (4-fluorophenyl) methyl] -3 - [(3,5-difluorophenyl) (methylsulfonyl) methyl- (RS)] azetidin-3-ol is obtained, in the form of a solid white.
  • Bis (4-fluorophenyl) bromomethane can be prepared according to the procedure described by BACHMANN WE, J. Am. Chem. Soc, 2135 (1933) from 4 g of 4,4'-difluorobenzydrol, 2.70 cm 3 of acetyl bromide and 14 cm 3 of a 33% hydrobromic acid solution in acetic acid .
  • Example 38 By operating as in Example 38 (method 1), starting with 1.22 g of 1- [bis (2-fluorophenyl) methyl] -3 - [(3,5-difluorophenyl) (methylsulfonyl) methyl- (RS)] azetidin-3-ol, 0.29 cm 3 of methanesulfonyl chloride and 1.1 g of 4-dimethylaminopyridine, obtained after chromatography on a column of silica gel (particle size 0.04-0.06 mm , diameter 3 cm, height 23 cm), under a pressure of 1 bar of argon with a mixture of ethyl acetate and cyclohexane (15/85 by volume) as eluent and collecting fractions of 60 cm 3 , 0.177 g of l- [bis (2-fluorophenyl) methyl] -3 - [(3,5-difluorophenyl) (methylsulfonyl) methylene]
  • Bis (2-fluorophenyl) bromomethane can be prepared according to the procedure described by BACHMANN WE, J. Am. Chem. Soc, 2135 (1933), from 1.80 g of 2,2'-difluorobenzydrol, 1.22 cm 3 of acetyl bromide and 6.5 cm 3 of a 33% hydrobromic acid solution in acetic acid.
  • the 2,2'-difluorobenzydrol can be prepared according to the following method: to a solution cooled to -70 ° C under argon of 8.8 g of 2-bromofluorobenzene in 100 cm 3 of tetrahydrofuran, 32 cm 3 are poured dropwise of n-butyllithium in 1.6M solution in hexane. After 10 minutes of stirring at -70 ° C, 2.1 cm 3 of ethyl formate is added slowly and the mixture is then stirred at -70 ° C for 30 minutes. The reaction medium is then brought to 0 ° C. and then added with 50 cm 3 of ethyl acetate and 100 cm 'of saturated ammonium chloride solution.
  • Example 38 By operating as in Example 38 (method 1), from 1.15 g of l- [bis (3-fluorophenyl) methyl] -3 - [(3,5-difluorophenyl) (methylsulfonyl) methyl- (RS)] azetidin-3-ol, 0.264 cm 3 of methanesulfonyl chloride, and 0.98 g of 4-dimethylaminopyridine, obtained after chromatography on a column of silica gel (particle size 0.06 - 0.200 mm, diameter 2 , 8 cm, height 25 cm), under a pressure of 1 bar of argon with a mixture of ethyl acetate and cyclohexane (15/85 by volume) as eluent and collecting fractions of 60 cm 3 , 0, 55 g of l- [bis (3-fluorophenyl) methyl] -3 - [(3,5- difluorophenyl) (methylsulfonyl)
  • L- [bis (3-fluorophenyl) methyl] -3 - [(3,5-difluorophenyl) (methylsulfonyl) methyl- (RS)] azetidin-3-ol can be prepared as follows: by operating according to Example 1 from 1.2 g of (3,5-difluorobenzyl) methylsulfone and 1.5 g of l- [bis (3-fluorophenyl) methyl] azetidin-3-one, obtained after purification on a gel column silica (particle size 0.06-0.200 mm, diameter 3.2 cm, height 30 cm), under a pressure of 1 bar of argon with a mixture of ethyl acetate and cyclohexane (2/8 by volume) as eluent and collecting 60 cm 3 fractions, 1.95 g of l- [bis (3-fluorophenyl) methyl] -3 - [(3,5-difluorophenyl) (
  • [Bis (3 -__ uorophenyl) methyl] amine can be prepared as follows: to a suspension of 1.27 g of lithium aluminum hydride in 80 cm 3 of tetrahydrofuran, it is poured under an atmosphere of 'argon in 30 minutes a solution of 5.17 g of 3,3'-difluorobenzophenone oxime in 30 cm 3 of tetrahydrofuran. After 5 hours of stirring at reflux, 1.3 cm 3 of water, 1.3 cm 3 of 4N sodium hydroxide, 2.6 cm 3 of water and then 50 cm of ethyl acetate are successively added. After drying over magnesium sulfate and concentration to dryness under reduced pressure (2.7 kPa), 4.9 g of [bis (3-fluorophenyl) methyl] amine are obtained, in the form of a yellow oil.
  • 3-3'-difluorobenzophenone oxime can be prepared according to the following procedure: in a solution of 5.0 g of 3,3'-difluorobenzophenone in 10 cm 3 of ethanol, a solution of 1 is poured dropwise, 6 g hydrochloride of hydroxylamine in 8 cm 3 of water, then add 1.2 g of sodium hydroxide pellets in small portions. The reaction mixture, brought to reflux for 10 minutes, is cooled to 20 ° C. and then acidified with 7.5 cm 3 of 4N hydrochloric acid. The oily precipitate obtained once triturated becomes a white solid which is filtered, washed with water and then dried at 35 ° C under reduced pressure (2.7 kPa). 5.17 g of 3.3'-difluorobenzophenone oxime are obtained in the form of a white solid.
  • the mixture of the two diastereoisomers l - [(4-chlorophenyl) (thiazol-2-yl) methyl- (RS)] - 3 - [(methylsulfonyl) (phenyl) methyl- (RS)] azetidin-3-ol, can be obtained in the following manner: by operating as in Example 39 from 4.47 g of (RS) - bromo (4-chlorophenyl) (thiazol-2-yl) methane and 4.31 g of 3- hydrochloride [(methylsulfonyl) (phenyl) methyl- (RS)] azetidin-3-ol and after chromatography on a column of silica gel (particle size 0.06-0.200 mm, diameter 5.6 cm, height 40 cm), under a pressure of 0.5 bar of argon with a mixture of ethyl acetate and cyclohexane (25/75 by volume) up to fraction 35 then with
  • (RS) -bromo (4-chlorophenyl) (thiazol-2-yl) methane can be prepared according to the procedure described by BACHMANN WE, J. Am. Chem. Soc, 2135 (1933), from 3.5 g of (RS) - (4-chlorophenyl) (2-thiazolyl) methanol, 3.81 g of acetyl bromide and 12.0 cm 3 of a solution 33% hydrobromic acid in acetic acid.
  • the mixture of the two diastereoisomers l - [(4-chlorophenyl) (thien-2-yl) methyl- (RS)] - 3 - [(3,5-difluorophenyl) (methylsulfonyl) methyl- (RS)] azetidin-3- ol can be prepared as follows: by operating as in Example 1 from 1.60 cm 3 of n-butyllithium 1.6N in solution in hexane, of 0.83 g of (3,5-difluorobenzyl) methylsulfone and 1.06 g of l - [(4-Chlorophenyl) (thien-2-yl) methyl- (RS)] azetidin-3-one, obtained after purification on a silica gel column (particle size 0.06-0.200 mm , diameter 2.8 cm, height 30 cm), under a pressure of 0.5 bar of argon with a mixture of ethyl
  • L - [(4-chlorophenyl) (thien-2-yl) methyl- (RS)] azetidin-3-one can be prepared by operating as follows: in a solution cooled to -70 ° C of 1.83 cm 3 of oxalyl chloride in 20 cm 3 of dichloromethane under argon, 3.04 cm 3 of dimethyl sulfoxide are poured in 10 minutes. After 30 minutes of stirring at -60 ° C., a solution of 5.2 g of l - [(4-chlorophenyl) (thien-2-yl) methyl- (RS)] azetidin-3- is poured in 20 minutes.
  • L - [(4-chlorophenyl) (thien-2-yl) methyl- (RS)] azetidin-3-ol can be prepared as follows: to a solution of 11.0 g of [(4-chlorophenyl ) (thien-2-yl) methyl- (RS)] amine in 80 cm 3 of ethanol is added 4.12 g of sodium bicarbonate. 4.03 cm 3 of epibromhydrin are added to the mixture heated to 65 ° C. After 8 p.m. stirring at 65 ° C., the cooled mixture is filtered and the filtrate concentrated to dryness under reduced pressure (2.7 Kpa).
  • [(4-chlorophenyl) (thien-2-yl) methyl- (RS)] amine can be prepared as follows: to a suspension cooled to 10 ° C of 4-chlorophenylmagnesium bromide (prepared from 19, 15 g of 4-bromochlorobenzene and 2.43 g of magnesium) in 120 cm 3 of anhydrous ethyl ether, a solution of 10.92 g of 2-thiophenecarbonitrile is slowly poured into 80 cm 3 of ethyl ether. After one hour of reflux, the mixture is cooled to 10 ° C, slowly added 40 cm 3 of methanol and then filtered through supercel.
  • 4-chlorophenylmagnesium bromide prepared from 19, 15 g of 4-bromochlorobenzene and 2.43 g of magnesium
  • a solution of 10.92 g of 2-thiophenecarbonitrile is slowly poured into 80 cm 3 of ethyl ether. After one hour of reflux, the mixture is cooled to
  • (+) - 1 - [(4-chlorophenyl) (thien-2-yl) methyl] azetidin-3-one can be prepared as described in Example 75, from 12.4 g of (+ ) -l - [(4-chlorophenyl) (thien-2-yl) methyl] azetidin-3-ol, 220 cm 3 of dichloromethane, 7.1 cm 3 of dimethyl sulfoxide,
  • (+) - 1 - [(4-chlorophenyl) (thien-2-yl) methyl] azetidin-3-ol can be prepared as described in Example 75, from 16.1 g of (+ ) - [(4-chlorophenyl) (thien-2-yl) methyl] amine, 130 cm 3 of ethanol, 5.9 cm 3 of epibromhydrin, and 6.05 g of sodium bicarbonate. After purification by chromatography, 11.5 g of (+) - 1 - [(4-chlorophenyl) (thien-2-yl) methyl] azetidin-3-ol are obtained in the form of a cream-colored oil.
  • (+) - 4 - [(chlorophenyl) (thié-2-yl) methyl] amine can be prepared as follows: to a solution of 109 g of [(4-chlorophenyl) (thién-2-yl ) methyl- (RS)] amine in 500 cm 3 of methanol, 73 g of D - (-) - tartaric acid are added. The mixture is concentrated to dryness under reduced pressure (2.7 kPa). The meringue obtained is taken up in 2.05 liters of a 90/10 ethanol-water mixture by volume. After 20 hours of slow stirring at 20 ° C, the crystalline suspension obtained is filtered, the crystals washed with the minimum of the same mixture of solvents, then dried.
  • (-) - 1 - [(4-chlorophenyl) (thien-2-yl) methyl] azetidin-3-one can be prepared as described in Example 75, from 11.4 g of (- ) -l - [(4-chlorophenyl) (thien-2-yl) methyl] azetidin-3-ol, 200 cm 3 of dichloromethane, 4.0 cm 3 of dimethylsulfoxide, 4.0 cm 3 of oxalyl chloride, and 19.5 cm 3 of triethylamine.
  • (-) - [(4-chlorophenyl) (thien-2-yl) methyl] amine can be prepared as follows: to a solution of 43 g of [(4-chlorophenyl) (thièn-2-yl) methyl - (RS)] amine in 200 cm 3 of methanol, 29 g of L - (+) - tartaric acid are added. The mixture obtained crystallizes in 2 hours at room temperature. The crystals are filtered, washed with 2 times 10 cm 3 of methanol.
  • Recrystallization is carried out with 500 cm 3 of an 80/20 mixture of ethanol-water by volume, the crystals are filtered, washed twice with 30 cm 3 of the same mixture of solvents, then dried under vacuum at 45 ° C. .
  • a final recrystallization is carried out with 350 cm 3 of an ethanol-water mixture 78/22 in volumes, leaving to stir for 20 hours at 20 ° C.
  • Example 2 By operating according to the procedure of Example 1 starting from 3.4 g of 1 -benzhydryl- 3 - [(ethylsulfonyl) (phenyl) methyl- (RS)] azetidin-3-ol, 0.72 cm 3 methanesulfonyl chloride and 3.8 g of 4-dimethylaminopyridine, after recrystall- lization in 40 cm 3 of acetonitrile, 1.9 g of 1 -benzhydry 1-3- [(ethylsulfonyl) (phenyl) methylene] azetidine in the form of crystals melting at 210 ° C.
  • 1-Benzhydryl-3 - [(ethylsulfonyl) (phenyl) methyl- (RS)] azetidin-3-ol can be obtained by operating according to the procedure described in Example 1 from 2.4 g of benzylethylsulfone, 2.2 cm 3 of diisopropylamine, 10 cm 3 of n-butyl lithium 1.6N in solution in hexane, 65 cm 3 of tetrahydrofuran and 3.1 g of 1 -benzhydryl azetidin-3-one.
  • the benzylethylsulfone can be prepared by operating according to the procedure of Example 2 from 6.3 g of benzylethylsulfide, 50 cm 3 of acetic acid, 50 cm 3 of water, 25 cm 3 of sulfuric acid 36N and 24.8 g of oxone R. 3.2 g of benzylethyl sulfone are obtained, by recrystallization from 20 cm 3 of ethyl ether, in the form of a solid melting at 86 ° C.
  • Benzylethylsulfide can be prepared in the following way: to a solution of 5 g of benzylmercaptan in 50 cm 3 of dimethylformamide under argon, 1.2 g of sodium hydride is added in small portions and then 3.36 cm 3 d 'ethyl iodide, maintaining a temperature below 45 ° C. The mixture is stirred for 2 hours then taken up in 200 cm 3 of ethyl ether. The organic phase is washed with 200 cm 3 of water and then 3 times 100 cm 3 of water, dried over magnesium sulphate and concentrated to dryness under reduced pressure (2.7 kPa). 6.3 g of benzylethylsulfide are obtained in the form of a pale yellow liquid.
  • Example 79 To a solution of 0.45 g of 1- [bis (4-chlorophenyl) methyl] -3 - ⁇ (methylsulfonyl) [3- (pentafluorophenoxycarbonyl) phenyl] methylene] azetidine in 5 cm 3 of dimethylformamide, 0.083 g of 1-amino-4-methylpiperazine. The mixture is stirred for 20 hours at ambient temperature then 40 cm 3 of ethyl acetate are added. The organic phase is washed with 4 times 20 cm 3 of water, dried over magnesium sulfate and concentrated to dryness under reduced pressure (2.7 kPa). The residue is triturated with 10 cm 3 of ethyl ether, filtered and then dried.
  • the mixture is stirred for 20 hours at room temperature and then taken up in 50 cm 3 of ethyl acetate.
  • the organic phase is washed with 100 cm 3 of water, 200 cm 3 of a saturated aqueous solution of sodium bicarbonate and then twice with 50 cm 3 of distilled water, dried over magnesium sulfate and concentrated to dryness under reduced pressure (2.7kpa).
  • the residue is chromatographed on a silica column (size 0.04-0.006mm, diameter 2 cm), eluting with a dichloromethane and ethanol mixture (99/1 by volume).
  • L- [bis (4-chlorophenyl) methyl] -3 - [(3-carboxyphenyl) (methylsulfonyl) methylene] azetidine can be prepared as follows: To a solution of 3.8 g l- [bis (4- chlorophenyl) methyl] -3 - [(3-cyanophenyl) (methylsulfonyl) methylene] azetidine in 5 cm 3 of acetic acid is added a 36% hydrochloric acid solution at a temperature of 50 ° C. Heating is continued for 48 hours then the mixture is evaporated to dryness under reduced pressure (2.7 Kpa). The residue is taken up in 30 cm 3 of ethanol and evaporated to dryness again.
  • 1 - [bis (4-chlorophenyl) methyl] -3 - [(3-cyanophenyl) (methylsulfonyl) methylene] azetidine can be prepared according to the procedure of Example 4, starting from 11 g of 1 - [bis (4-chlorophenyl) methyl] -3 - [(3-cyanophenyl) (methylsulfonyl) methyl- (RS)] azetidin-3-ol, 150 cm 3 of dichloromethane, 2.54 cm 3 of methanesulfonyl chloride and 10 , 7 g of 4-dimethylaminopyridine, at room temperature for 3 hours.
  • L- [bis (4-chlorophenyl) methyl] -3 - [(3-cyanophenyl) (methylsulfonyl) methyl- (RS)] azetidin-3-ol can be prepared as follows: In a solution of 17, 6 cm 3 of 1.6M n-butyllithium in hexane, in 30 cm 'of tetrahydrofuran under argon, and cooled to -70 ° C, is added a solution of 5 g of 3-cyanobenzyl methyl sulfone in 500 cm 3 tetrahydrofuran in 15 minutes. The mixture is stirred for 1 hour 30 minutes.
  • the (3-cyanobenzyl) methylsulfone can be prepared in the following manner: From a solution of 20.2 g of 3-chloroméfhylbenzonitrile in 200 cm 3 of ethanol, 17.4 g of sodium methanesulfinate are added to 85%. The mixture is stirred for 20 hours at reflux, then taken up in 500 cm 3 of ethyl acetate and 500 cm 3 of water. The insoluble material is filtered, the organic phase in the filtrate is dried over magnesium sulfate and evaporated to dryness under reduced pressure (2.7 Kpa). The solid obtained is triturated with 100 cm 3 of ethyl ether. After filtration and drying of the solid, 21 g of (3-cyanobenzyl) methylsulfone are obtained in the form of white crystals, melting at 165 ° C.
  • the 3-chloromethylbenzonitrile can be prepared as follows: For 3 hours, 32 g of 3-chloromethylbenzoamide in 200 cm 3 of phosphorus oxychloride are heated to 95 ° C., then charge 1 liter of ice, stir for 1 hour, extract the mixture with 500 cm 3 of dichloromethane. The organic phase is washed with 200 cm 3 of water, dried over magnesium sulfate and evaporated to dryness under reduced pressure (2.7 Kpa). 20.2 g of 3-chloromethylbenzonitrile are obtained in the form of a white solid.
  • azetidin-3-ol can be obtained according to the procedure described in example 1, from 1.5 g of l- [bis (thien-2-yl) methyl] azetidin-3-one , 4 cm 3 of n-butyl lithium at 1.6 N in hexane, 1.3 g of (3,5-difluorobenzyl) methylsulfone and 40 cm 3 of tetrahydrofuran. After purification by chromatography, 2.2 g of 1- [bis (thien-2-yl) methyl] -3 - [(3,5-difluorophenyl) (methylsulfonyl) methyl- (RS)] azetidin- are obtained. 3-ol, in the form of white crystals melting at 145 ° C
  • the l- [bis-thien-2-yl) methyl] azetidin-3-one can be prepared by operating as described in Example 75, from 4 g of l- [bis (thien-2- yl) methyl] azetidin-3-ol, 2.6 cm 3 of dimethyl sulfoxide, 7.7 cm 3 of triethylamine, 7.7 cm 3 of oxalyl chloride, and 100 cm 3 of dichloromethane.
  • the residue obtained is purified by chroma- topography on a column of silica gel (particle size 0.04-0.06 mm, diameter 3 cm, height 30 cm) with a cyclohexane and ethyl acetate mixture (1/1 by volume) as eluent.
  • the fractions obtained are evaporated to dryness under reduced pressure (2.7 Kpa).
  • 3.2 g of l- [bis (thien-2-yl) methyl] azetidin-3-one are obtained in the form of cream crystals melting at 70 ° C.
  • the l- [bis (thien-2-yl) methyl] azetidin-3-ol can be prepared by operating as described in Example 75, starting from 6 g of l- [bis (thien-2- yl) methyl] amine, 2.5 cm 3 of epibromhydrin, 2.6 g of sodium bicarbonate and 50 cm 3 of ethanol. 4 g of 1- [bis (thien-2-yl) methyl] azetidin-3-ol are obtained in the form of beige crystals, melting at 11 ° C.
  • the l- [bis (thien-2-yl) methyl] amine can be prepared as follows: to a suspension cooled under argon to 10 ° C of thien-2-ylmagnesium bromide (prepared from 1.29 g of magnesium and 3.22 cm 3 of 2-bromo thiophene in 75 cm 3 of diethyl oxide), is poured drop by drop a solution of 5 cm 3 of thien-2-ylcarbonitrile in 50 cm 3 of diethyl ether. After 1 hour and 30 minutes of reflux, the reaction medium is cooled to 5 ° C. and then 20 cm 3 of methanol are poured in dropwise, the suspension is filtered, the solid is washed with methanol. The filtrate obtained a brown solution.
  • l- (bis-p-tolylmethyl) -3 - [(methylsulfonyl) (phenyl) methyl- (RS)] azetidin-3-ol can be prepared according to the procedure described in Example 39, starting from 0, 59 g of bromo (bis-p-tolyl) methane, 20 cm 3 of acetonitrile, 0.3 g of potassium carbonate and 0.6 g of 3 - [(methylsulfonyl) (phenyl) methyl- (RS) hydrochloride ] azetidin-3-ol.
  • Bromo (di-p-tolyl) methane can be prepared according to the procedure described by BACHMANN W.E., J.Am.Chem.Soc, 2135, (1933).
  • 3 - [(methylsulfonyl) (phenyl) methyl- (RS)] azetidin-3-ol hydrochloride can be prepared according to the procedure described in Example 39 from 7 g of 3- [(methylsulfonyl) ( phenyl) methyl- (RS)] - 1- (vinyloxycarbonyl) azetidin-3-ol, 35 cm 3 of dioxane, 35 cm 3 of a 6.2N solution of hydrochloric acid in dioxane. 5 g of 3 - [(methylsulfonyl) (phenyl) methyl- (RS)] azetidin-3-ol hydrochloride are obtained in the form of a white solid.
  • the organic phase is washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate, then evaporated to dryness under reduced pressure (2.7 kpa).
  • the white meringue obtained is purified on a column of silica gel (particle size 0.04-0.06 mm, diameter 3.2 cm, height 17 cm) with a cyclohexane and ethyl acetate mixture as eluent (60/40 in volume).
  • (-) - l - [(4-chlorophenyl) (4-formylphenyl) methyl] -3 - [(3,5-difluorophenyl) methylsulfonylmethylenejetidine can be prepared as follows: To a solution 0.83 g of (+) - l - ⁇ (4-chlorophenyl) [4- (1,3-dioxolan-2-yl) phenyl] methyl ⁇ -3 - [(3,5- difluorophenyl) (methylsulfonyl) methylene] azetidine in 5 cm 3 of tetrahydrofuran, 3.32 cm 3 of a 5N hydrochloric acid solution are poured in and then left to stir for 20 hours.
  • (+) - l - ⁇ (4-chlorophenyl) [4- (1,3-dioxolan-2-yl) phenyl] methyl ⁇ -3 - [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine can be obtained as follows: To a solution of 2.42 g of the mixture of the two diastereoisomers 3-acetoxy-1 - ⁇ (4-chlorophenyl) [4- (1,3-dioxolan-2-yl) phenyl] methyl- (R *) ⁇ - 3 - [(3,5-difluorophenyl) (methylsulfonyl) methyl- (R *)] azetidine and 3-acetoxy-1 - ⁇ (4-chlorophenyl) [4- (l, 3- dioxolan-2-yl) phenyl] methyl- (R *) ⁇ - 3
  • the reaction medium is diluted with ethyl acetate, washed with water and with a saturated aqueous solution of sodium chloride.
  • the organic phase is dried over magnesium sulfate, filtered and evaporated to dryness under reduced pressure.
  • the crude product is purified on a column of silica gel (particle size 0.04-0.06 mm, diameter 4.8 cm, height 17.5 cm) with a cyclohexane and ethyl acetate mixture as eluent (80/20 in volumes).
  • azetidine can be prepared as follows: to a solution of 1.08 g of 3-5 difluorobenzyl methyl sulfone under argon cooled to -70 ° C, one drip 3.27 cm 3 of n-butyllithium, stir for 1 hour at -70 ° C then drip a solution of 1.80 g of (+) - l - ⁇ (4-chlorophenyl) [4 - (1,3-dioxolan-2-yl) phenyl] methyl ⁇ azetidin-3-one in 10 cm 3 of tetrahydrofuran.
  • (+) - 1 - ⁇ (4-chlorophenyl) [4- (1, 3-dioxolan-2-yl) phenyl] methyl ⁇ azetidin-3-one can be prepared as follows: to a solution of 1 , 38 g of (+) - l - ⁇ (4-chlorophenyl) [4- (1,3-dioxolan-2-yl) phenyl] methyl ⁇ azetidin-3-ol in 20 cm 3 of anhydrous dimethylsulfoxide 2.24 cm 3 of triethylamine are poured under argon and then 1.65 g of a solution of pyridine sulfide trioxide complex in 20 cm 3 of anhydrous dimethyl sulfoxide are added dropwise.
  • (+) - 1 - ⁇ (4-chlorophenyl) [4- (1, 3 -dioxolan-2-yl) phenyl] methyl ⁇ azetidin-3 -ol can be described according to the procedure described in Example 75, from 4.43 g of (+) - ⁇ (4-chlorophenyl) [4- (1,3-dioxolan-2-yl) phenyl] methyl ⁇ amine, 40 cm 3 of absolute ethanol, 1.25 cm 3 epibromhydrin, and 1.28 g of sodium bicarbonate.
  • (+) - ⁇ (4-chlorophenyl) [4- (1,3-dioxolan-2-yl) phenyl] methyl ⁇ chiral amine may be obtained in the following manner: in a suspension of 18.16 g of (R *) - [(4-chlorophenyl) (4-formylphenyl) methyl] chiral hydrochloride, in 1000 cm 3 of toluene, 3.95 cm 3 of ethylene glycol are poured in and 0.82 g of acid are added paratoluenesulfonic monohydrate.
  • (R *) - [(4-chlorophenyl) (4-formylphenyl) methyl] chiral amine hydrochloride can be prepared as follows: to a solution of 51.4 g of the diastereoisomother N - ⁇ (4 -chlorophenyl) [4- (diethoxymethyl) phenyl] methyl- (R *) ⁇ - (R) -2-phenyl-glycinol in 660 cm 3 of anhydrous dichloromethane, poured 330 cm 3 of methanol, cools the mixture with a bath of ice, add 60.96 g of lead tetraacetate, stir for 5 minutes then pour 1 liter of a phosphate buffer solution at pH 7.
  • N - ⁇ (4-chlorophenyl) [4- (diethoxymethyl) phenyl] methyl- (R *) ⁇ - (R) -2-phenylglycinol can be prepared as follows: in a solution cooled to -70 ° C, under argon, of 87.7 g of 4-bromochlorobenzene, 286 cm 3 of 1.6M n butyl lithium are poured in dropwise into hexane, the mixture is stirred for 15 minutes at -70 ° C.
  • (R) -N- [4- (diethoxymethyl) benzylidene] -2-phenylglycinol can be prepared as follows: To a white suspension of 24.7g of (R) - (-) - 2-phenyl glycinol in 500 cm 3 of toluene 35.9 cm 3 of 4- (diethoxymethyl) benzaldehyde is poured. The cloudy yellow solution is heated at reflux for 6 hours 30 minutes, then stirred at room temperature for 20 hours.
  • Example 2 By operating according to the procedure of Example 1, starting from 5.6 g of 1- [bis (4-chlorophenyl) methyl] -3- ⁇ [3- (N-tertbutyloxycarbonyl-N- methylamino) phenyl] (methylsulfonyl) methyl- (RS) ⁇ azetidin-3-ol, 100 cm 3 of dichloromethane, 1.59 g of methanesulfonyl chloride and 4.5 g of 4-dimethylaminopyridine. The mixture is left to stir for 3 hours at room temperature.
  • the crude product obtained is purified by chromatography on a column of silica gel (particle size 0.04-0.06 mm, diameter 4 cm and weight in silica 250 g), eluting under a pressure of 0.5 bar of nitrogen with a mixture of ethyl acetate / cyclohexane (30/70 by volume) and collecting 100 cm 3 fractions. Fractions 12 to 18 are combined, concentrated to dryness under reduced pressure (2.7 kpa).
  • the crude product is purified by chromatography on a column of silica gel (particle size 0.04-0.06 mm, diameter 4 cm, weight in silica 250 g), eluting under a pressure of 0.5 bar of nitrogen with dichloromethane then with a dichloromethane and ethanol mixture (99/1 by volume) and collecting 500 cm 3 fractions. Fractions 10 to 16 are combined, concentrated to dryness under near- reduced pressure (2.7 kPa).
  • Example 2 The procedure is as in Example 1, starting from 0.40 g of a mixture of two diastereoisomers l - [(4chlorophenyl) (thiazol-2-yl) methyl- (RS)] - 3 - [(3,5 -difluorophenyl) (methylsulfonyl) methyl- (RS)] azetidin-3-ol, 0.10 cm 3 of methanesulfonyl chloride and 0.37 g of 4-dimethylaminopyridine, obtained after chromatography on a column of silica gel (particle size 0.06-0.200 mm, diameter 1.2 cm, height 20 cm), under a pressure of 1 bar of argon with a mixture of ethyl acetate and cyclohexane (40/60 by volume) as eluent and collecting 20 cm 3 fractions, 0.13 g of (RS) -l - [(4-chlorophenyl) (thiazol-2
  • the mixture of the two diastereoisomers l - [(4-chlorophenyl) (thiazol-2-yl) methyl- (RS)] - 3 - [(3,5-difluorophenyl) (methylsulfonyl) methyl- (RS)] azetidin-3- ol, can be obtained as follows: by operating as in Example 72, from 1.01 g of (RS) -bromo (4-chlorophenyl) thiazol-2-ylmethane and 0.55 g of hydrochloride (RS) -3 - [(3,5-difluorophenyl) (methylsulfonyl) methyl] azetidin-3-ol and after chromatography on a column of silica gel (particle size 0.06-0.200 mm, diameter 4.4 cm, height 38 cm), under a pressure of 0.5 bar of argon, eluting with a mixture of ethyl a
  • reaction mixture is washed with water and then the organic phase is dried over magnesium sulfate, concentrated to dryness under vacuum (2.7 kPa).
  • the residue obtained is chromatographed on a column of silica gel (particle size 0.06-0.200 mm, diameter 1.2 cm, height 30 cm), under a pressure of 0.1 bar of argon, eluting with dichloromethane and then with a mixture of dichloromethane and methanol (97.5 / 2.5 by volume) and collecting 3 cm 3 fractions. Fractions 12 to 40 are combined and then concentrated to dryness under reduced pressure (2.7 kPa).
  • the mixture of the 2 diastereoisomers (forms A) l - ⁇ (R *) - [4- (chloromethyl) phenyl] (4-chlorophenyl) methyl ⁇ -3 - [(R) - (3,5-difluorophenyl) (methylsulfonyl) methyl)] azetidin-3 -ol, and 1 - ⁇ (R *) - [4- (chloromethyl) phenyl] (4-chlorophenyl) methyl ⁇ -3 - [(S) - (3, 5-di-fluorophenyl) (methylsulfonyl) methyl)] azetidin-3-ol, can be prepared by operating as follows: To a solution of 0.20 g of the mixture of the 2 diastereoisomers (forms A) l - ⁇ (R *) - (4-chlorophenyl) [4- (hydroxymethyl) pheny
  • the mixture of the 2 diastereoisomers (forms A) l - ⁇ (R *) - (4-chlorophenyl) [4- (hydroxymethyl) phenyl] methyl ⁇ -3 - [(R) - (3, 5 -difluorophenyl) (methylsulfonyl) methyl)] azetidin-3-ol and l - ⁇ (R *) - (4-chlorophenyl) [4- (hydroxymethyl) phenyl] methyl ⁇ -3- [(S) - (3,5-difluorophenyl) ( methylsulfonyl) methyl)] azetidin-3-ol, can be prepared by operating as follows: 0.58 g of the mixture of 2 diastereoisomers (forms A) 3- in a solution maintained under argon and cooled to -30 ° C.
  • the l - ⁇ (R *) - (4-chlorophenyl) [4- (methoxycarbonyl) phenyl] methyl ⁇ azetidin-3-one, isomer form A can be prepared by operating as described in Example 40, from 0.55 cm 3 of oxalyl chloride, 25 cm 3 of dichloromethane, 0.90 cm 3 of dimethyl sulfoxide, 1.75 g of l - ⁇ (4-chlorophenyl) [4- (methoxycarbonyl) phenyl] methyl ⁇ azetidin-3-ol, and 2.70 cm 3 of triethylamine.
  • the l - ⁇ (R *) - (4-chlorophenyl) [4- (methoxycarbonyl) phenyl] methyl ⁇ azetidin-3-ol, isomer form A can be prepared by operating according to the procedure described by KATRITZKY AR et al. , in J. Heterocycl. Chem., (1994), 271 from 2.0 g of (+) - 4 - [(R *) - amino- (4-chlorophenyl) methyl] methyl benzoate, 30 cm 3 of ethanol, 0 , 60 g of sodium hydrogencarbonate, and 0.60 cm 3 of epibromhydrin.
  • Methyl (+) - 4 - [(R *) - amino- (4-chlorophenyl) methyl] benzoate can be prepared as follows: To a solution of 9.2 g of 4 - [(RS) -amino- (4-chlorophenyl) methyl] methyl benzoate in 10 cm 3 of methanol, 2.51 g of D - (-) - tartaric acid are added. The solution is concentrated to dryness under reduced pressure (2.7 kPa). The cream meringue obtained is dissolved in 50 cm 3 of ethanol containing 5% water and the resulting solution is left to crystallize for 20 hours at 20 ° C.
  • the crystals are filtered, washed with ethanol at 5% water, drained, then dried under reduced pressure (2.7 kPa). 3.4 g of white crystals are obtained, which are called “A crystals” [and which are stored for the subsequent preparation of the second (-) - 4 - [(R *) - amino- (4-chlorophenyl) enantiomer. ) methyl] methyl benzoate)].
  • the mother liquors are concentrated to dryness, and a white meringue (8.1 g) is obtained which is dissolved in 100 cm 3 of ethyl acetate. To the solution obtained is added 50 cm 3 of sodium hydroxide IN, stirred and decanted.
  • Methyl 4 - [(RS) -amino- (4-chlorophenyl) methyl] benzoate can be prepared by operating as follows: To a suspension of 16.3 g of 4 - [(RS) -phthalimido- (4 - methyl chlorophenyl) methyl] benzoate in 200 cm 3 of methanol, 3.9 cm 3 of hydrazine hydrate are added. After 5 hours of stirring at reflux temperature and then 20 hours at 20 ° C, the reaction mixture is filtered, the filtrate is concentrated to dryness under reduced pressure (2.7 kPa). The residue obtained is taken up in a mixture of 200 cm 3 of water and 200 cm 3 of ethyl acetate.
  • Methyl 4 - [(RS) -phthalimido- (4-chlorophenyl) methyl] benzoate can be prepared by operating as follows: To a solution of 11.6 g of 4 - [(RS) -bromo- ( Methyl 4-chlorophenyl) methyl] benzoate, in 70 cm 3 of dimethylformamide, 12.6 g of potassium phthalimide are added. After 3 hours of stirring at reflux temperature, the reaction mixture is cooled to 20 ° C. then added with 300 cm 3 of ethyl acetate and 300 cm 3 of water.
  • Methyl 4 - [(RS) -bromo- (4-chlorophenyl) methyl] benzoate can be prepared as follows: To a solution of 17.4 g of 4 - [(RS) - (4- methyl chlorophenyl) (hydroxy) methyl] benzoate in 200 cm 3 of acetonitrile, 10.18 g of NN'-carbonyldiimidazole and 54.3 cm 3 of allyl bromide are added. After 30 minutes of stirring at 20 ° C, the reaction mixture is brought to reflux for 2 hours, stirred for 20 hours at 20 ° C and concentrated almost to dryness under reduced pressure (2.7 kPa).
  • Methyl 4 - [(RS) - (4-chlorophenyl) (hydroxy) methyl] benzoate can be prepared by operating as follows: To a suspension of 2.75 g of 4- (4-chlorobenzoyl) benzoate of methyl, in 200 cm 3 of methanol at 20 ° C., 1.21 g of sodium borohydride are added slowly in small fractions (the medium heats up to 50 ° C.). After 20 hours of stirring at 20 ° C, the reaction mixture is concentrated to reduced volume and then added with 150 cm 'of dichloromethane and with stirring of 100 cm' of 0.5N hydrochloric acid.
  • Methyl 4- (4-chlorobenzoyl) benzoate can be prepared by operating as follows: In a solution cooled to -22 ° C of 19.3 g of terephthalic acid chloride monomethylester in 200 cm 3 of tetrahydrofuran, 27.4 cm 3 of tri n-butylphosphine are added under argon. After 20 minutes of stirring at -22 ° C, is poured while maintaining this temperature, a solution of 4-chlorophenylmagnesium bromide (prepared from 19.15 g of bromo-4-chlorobenzene, 2.43 g of magnesium and an iodine crystal in 100 cm 3 of diethyl ether at reflux).
  • Example 87 The procedure is as described in Example 87, starting from 0.05 g of l - ⁇ (R *) - [4- (chloromethyl) phenyl] - (4-chlorophenyl) methyl ⁇ -3 - [(3 , 5-difluorophenyl) (methylsulfonyl) methylene] azetidine, form A isomer, 1.0 cm 3 of dichloromethane, and 0.025 g of 3,3-dimethylpiperidine.
  • the crude product is chromatographed on a column of silica gel (particle size 0.06-0.200 mm, diameter 8 mm, height 8 cm), eluting with 80 cm 3 of dichloromethane and then eluting with a mixture of dichloromethane and methanol (95 / 5 by volume), collecting 2.5 cm 3 fractions as soon as this eluting mixture is used. Fractions 3 to 8 are combined and then concentrated to dryness under reduced pressure (2.7 kPa).
  • Example 87 The procedure is as described in Example 87, starting from 0.05 g of l - ⁇ (R *) - [4- (chloromethyl) phenyl] - (4-chlorophenyl) methyl ⁇ -3 - [(3 , 5-difluorophenyl) (methylsulfonyl) methylene] azetidine, isomer form A) methylsulfonyl methyl, 1.0 cm 3 of dichloromethane, and 0.025 g of thiomorpholine.
  • the crude product is chromatographed on a column of silica gel (particle size 0.06-0.200 mm, diameter 8 mm, height 8 cm), eluting with 80 cm 3 of dichloromethane, then with a mixture of dichloromethane and methanol (95/5 by volume), collecting 2.5 cm 3 fractions as soon as this eluting mixture is used. Fractions 3 to 8 are combined and then concentrated to dryness under reduced pressure (2.7 kPa).
  • Example 87 The procedure is as described in Example 87, starting from 0.05 g of - ⁇ (R *) - [4- (chloromethyl) phenyl] - (4-chlorophenyl) methyl ⁇ -3 - [(3, 5-difluorophenyl) (methylsulfonyl) methylene] azetidine, isomer form A, 1.0 cm 3 of dichloromethane, and 0.025 g of N-cyclohexyl-N-ethyl-amine.
  • the crude product is chromatographed on a column of silica gel (particle size 0.06-0.200 mm, diameter 8 mm, height 8 cm), eluting with 80 cm 3 of dichloromethane, then with a mixture of dichloromethane and methanol (95/5 by volume), collecting 2.5 cm 3 fractions as soon as this eluting mixture is used. Fractions 5 to 8 are combined and then concentrated to dryness under reduced pressure (2.7 kPa).
  • Example 87 The procedure is as described in Example 87, starting from 0.05 g of l - ⁇ (R *) - [4- (chloromethyl) phenyl] - (4-chlorophenyl) methyl ⁇ -3 - [(3 , 5-difluorophenyl) (methylsulfonyl) methylene] azetidine, isomer form A, 1.0 cm 3 of dichloromethane, and 0.032 g of 4- (ethoxycarbonyl) piperazine.
  • the crude product is chromatographed on a column of silica gel (particle size 0.06-0.200 mm, diameter 8 mm, height 8 cm), eluting with 80 cm 3 of dichloromethane, then with a mixture of dichloromethane and methanol (95/5 by volume), collecting 2.5 cm 3 fractions as soon as this eluting mixture is used. Fractions 2 to 8 are combined and then concentrated to dryness under reduced pressure (2.7 kPa).
  • Example 87 The procedure is as described in Example 87, starting from 0.05 g of l - ⁇ (R *) - [4- (chloromethyl) phenyl] - (4-chlorophenyl) methyl ⁇ -3 - [(3 , 5-difluorophenyl) (methylsulfonyl) methylene] azetidine, form A isomer, 1.0 cm 3 of dichloromethane, and 0.023 g of N-cyclopropyl-N-propyl-amine.
  • the crude product is chromatographed on a column of silica gel (particle size 0.06-0.200 mm, diameter 8 mm, height 8 cm), eluting with 80 cm 3 of dichloromethane, then with a mixture of dichloromethane and methanol (95 / 5 by volume), collecting 2.5 cm fractions as soon as this eluting mixture is used. Fractions 3 to 9 are combined and then concentrated to dryness under reduced pressure (2.7 kPa).
  • the crude product is chromatographed on a column of silica gel (particle size 0.06-0.200 mm, diameter 8 mm, height 8 cm), eluting with 80 cm 3 of dichloromethane, then with a mixture of dichloromethane and methanol (95/5 by volume), collecting 2.5 cm 3 fractions as soon as this eluting mixture is used. Fractions 2 to 8 are combined and then concentrated to dryness under reduced pressure (2.7 kPa).
  • Example 87 The procedure is as described in Example 87, starting from 0.05 g of l - ⁇ (R *) - [4- (chloromethyl) phenyl] - (4-chlorophenyl) methyl ⁇ -3 - [(3 , 5-difluorophenyl) (methylsulfonyl) methylene] azetidine, form A isomer, 1.0 cm 3 of dichloromethane, and 0.027 g of bis- (2-methoxyethyl) amine.
  • the crude product is chromatographed on a column of silica gel (particle size 0.06-0.200 mm, diameter 8 mm, height 8 cm), eluting with 80 cm 3 of dichloromethane, then with a dichloromethane and methanol mixture (95/5 by volume), collecting 2.5 cm 3 fractions as soon as this eluting mixture is used. Fractions 3 to 10 are combined and then concentrated to dryness under reduced pressure (2.7 kPa).
  • Example 87 The procedure is as described in Example 87, starting from 0.05 g of l - ⁇ (R *) - [4- (chloromethyl) phenyl] - (4-chlorophenyl) methyl ⁇ -3 - [(3 , 5-difluorophenyl) (methylsulfonyl) methylene] azetidine, isomer form A, 1.0 cm 3 of dichloromethane, and 0.020 g of di-n-propylamine.
  • the crude product is chromatographed on a column of silica gel (particle size 0.06-0.200 mm, diameter 8 mm, height 8 cm), eluting with 80 cm 'of dichloromethane, then with a mixture of dichloromethane and methanol (95/5 by volume), collecting 2.5 cm 3 fractions as soon as this eluting mixture is used. Fractions 3 to 8 are combined and then concentrated to dryness under reduced pressure (2.7 kPa).
  • Example 87 The procedure is as described in Example 87, starting from 0.05 g of l - ⁇ (R *) - [4- (chloromethyl) phenyl] - (4-chlorophenyl) methyl ⁇ -3 - [(3 , 5-difluorophenyl) (methylsulfonyl) methylene] azetidine, form A isomer, 1.0 cm 3 of dichloromethane, and 0.017 g of piperidine.
  • the crude product is chromatographed on a column of silica gel (particle size 0.06-0.200 mm, diameter 8 mm, height 8 cm), eluting with 80 cm 'of dichloromethane, then with a mixture of dichloromethane and methanol (95/5 by volume), collecting 2.5 cm 'fractions as soon as this eluting mixture is used. Fractions 5 to 10 are combined and then concentrated to dryness under reduced pressure (2.7 kPa).
  • Example 87 The procedure is as described in Example 87, starting from 0.05 g of l - ⁇ (R *) - [4- (chloromethyl) phenyl] - (4-chlorophenyl) methyl ⁇ -3 - [(3 , 5-difluorophenyl) (methylsulfonyl) methylene] azetidine, isomer form A, 1.0 cm 3 of dichloromethane, and 0.020 g of N-methylpiperazine.
  • the crude product is chromatographed on a column of silica gel (particle size 0.06-0.200 mm, diameter 8 mm, height 8 cm), eluting with 80 cm 3 of dichloromethane, then with a mixture of dichloromethane and methanol (95/5 by volume), collecting 2.5 cm fractions as soon as this eluting mixture is used. Fractions 3 to 9 are combined and then concentrated to dryness under reduced pressure (2.7 kPa).
  • Example 87 The procedure is as described in Example 87, starting from 0.05 g of l - ⁇ (R *) - [4- (chloromethyl) phenyl] - (4-chlorophenyl) methyl ⁇ -3 - [(3 , 5-difluorophenyl) (methyl- sulfonyl) methylene] azetidine, form A isomer, 1.0 cm 'of dichloromethane, and 0.018 g of morpholine.
  • the crude product is chromatographed on a column of silica gel (particle size 0.06-0.200 mm, diameter 8 mm, height 8 cm), eluting with 80 cm 3 of dichloromethane, then with a mixture of dichloromethane and methanol (95/5 by volume), collecting 2.5 cm 3 fractions as soon as this eluting mixture is used. Fractions 3 to 8 are combined and then concentrated to dryness under reduced pressure (2.7 kPa).
  • Example 87 The procedure is as described in Example 87, starting from 0.05 g of l - ⁇ (R *) - [4- (chloromethyl) phenyl] - (4-chlorophenyl) methyl ⁇ -3 - [(3 , 5-difluorophenyl) (methylsulfonyl) methylene] azetidine, isomer form A, 1.0 cm 3 of dichloromethane, and 0.020 cm 3 of D-prolinol.
  • the crude product is chromatographed on a column of silica gel (particle size 0.06-0.200 mm, diameter 8 mm, height 8 cm), eluting with 80 cm 3 of dichloromethane, then with a mixture of dichloromethane and methanol (95/5 by volume), collecting 2.5 cm 3 fractions as soon as this eluting mixture is used. Fractions 3 to 8 are combined and then concentrated to dryness under reduced pressure (2.7 kPa).
  • Example 87 The procedure is as described in Example 87, starting from 0.05 g of l - ⁇ (R *) - [4- (chloromethyl) phenyl] - (4-chlorophenyl) methyl ⁇ -3 - [(3 , 5 -difluorophenyl) (methylsulfonyl) methylene] azetidine, isomer form A, 1.0 cm 3 of dichloromethane, and 0.015 g of diethylamine.
  • the crude product is chromatographed on a column of silica gel (particle size 0.06-0.200 mm, diameter 8 mm, height 8 cm), eluting with 80 cm 'of dichloromethane, then with a mixture of dichloromethane and methanol (95/5 by volume), collecting 2.5 cm 3 fractions as soon as this eluting mixture is used. Fractions 4 to 9 are combined and then concentrated to dryness under reduced pressure (2.7 kPa).
  • Example 87 The procedure is as described in Example 87, starting from 0.05 g of l - ⁇ (R *) - [4- (chloromethyl) phenyl] - (4-chlorophenyl) methyl ⁇ -3 - [(3 , 5 -difluorophenyl) (methylsulfonyl) methylene] azetidine, isomer form A, 1.0 cm 3 of dichloromethane, and 0.026 g of N- (hydroxyethyl) piperazine.
  • the crude product is chromatographed on a column of silica gel (particle size 0.06-0.200 mm, diameter 8 mm, height 8 cm), eluting with 80 cm 3 of dichloromethane, then with a mixture of dichloromethane and methanol (95/5 by volume), collecting 2.5 cm 3 fractions as soon as this eluting mixture is used. Fractions 3 to 10 are combined and then concentrated to dryness under reduced pressure (2.7 kPa).

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PCT/FR1999/002147 1998-09-11 1999-09-09 Derives d'azetidine, leur preparation et les medicaments les contenant WO2000015609A1 (fr)

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BR9913592-2A BR9913592A (pt) 1998-09-11 1999-09-09 Compostos, processo de preparação dos compostos, e, composições farmacêuticas
PL346530A PL198526B1 (pl) 1998-09-11 1999-09-09 Pochodne azetydyny, sposób ich wytwarzania i kompozycje je zawierające
AU55232/99A AU772025B2 (en) 1998-09-11 1999-09-09 Azetidine derivatives, preparation and medicines containing them
CA002342739A CA2342739C (fr) 1998-09-11 1999-09-09 Derives d'azetidine, leur preparation et les medicaments les contenant
IL14176999A IL141769A0 (en) 1998-09-11 1999-09-09 Azetidine derivatives, preparation and medicines containing them
JP2000570149A JP4767413B2 (ja) 1998-09-11 1999-09-09 アゼチジン誘導体、それらの製造およびそれらを含有する薬剤
DK99941728T DK1112251T3 (da) 1998-09-11 1999-09-09 Azetidinderivater, deres fremstilling og medikamenter indeholdende disse derivater
DE69907698T DE69907698T2 (de) 1998-09-11 1999-09-09 Azetidinderivate, deren herstellung und sie enthaltende arzneimittel
EP99941728A EP1112251B1 (de) 1998-09-11 1999-09-09 Azetidinderivate, deren herstellung und sie enthaltende arzneimittel
AT99941728T ATE239703T1 (de) 1998-09-11 1999-09-09 Azetidinderivate, deren herstellung und sie enthaltende arzneimittel
HU0103341A HUP0103341A3 (en) 1998-09-11 1999-09-09 Azetidine derivatives, preparation and pharmaceutical compositions thereof
IL141769A IL141769A (en) 1998-09-11 2001-03-01 Azetidine derivatives, their preparation and medicines containing them
NO20011216A NO321480B1 (no) 1998-09-11 2001-03-09 Azetidinderivater, fremgangsmate for fremstilling og farmasoytiske preparater inneholdende forbindelsene.
US09/803,723 US6518264B2 (en) 1998-09-11 2001-03-09 Azetidine derivatives, their preparation and medicaments containing them
US10/320,344 US6858603B2 (en) 1998-09-11 2002-12-16 Acetindine derivatives, their preparation and medicaments containing them
US10/870,274 US20040235816A1 (en) 1998-09-11 2004-06-17 Azetidine derivatives, their preparation and medicaments containing them
AU2004203078A AU2004203078B2 (en) 1998-09-11 2004-07-08 Azetidine derivatives, their preparation and medicaments containing them
US11/420,238 US20060270649A1 (en) 1998-09-11 2006-05-25 Azetidine derivatives, their preparation and medicaments containing them

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CN115124447A (zh) * 2022-08-29 2022-09-30 山东诚创蓝海医药科技有限公司 一种3-氮杂环丁酮盐酸盐的制备方法

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PL198526B1 (pl) 2008-06-30
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CZ2001883A3 (en) 2001-06-13
AR021483A1 (es) 2002-07-24
DE69907698T2 (de) 2004-03-25
CA2342739C (fr) 2009-09-08
CN1149191C (zh) 2004-05-12
DE69907698D1 (de) 2003-06-12
EP1112251B1 (de) 2003-05-07
AU772025B2 (en) 2004-04-08
CA2342739A1 (fr) 2000-03-23
CZ301446B6 (cs) 2010-03-03
ATE239703T1 (de) 2003-05-15
AU5523299A (en) 2000-04-03
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MY119150A (en) 2005-04-30
MA26685A1 (fr) 2004-12-20
TNSN99168A1 (fr) 2005-11-10
FR2783246A1 (fr) 2000-03-17
ES2197666T3 (es) 2004-01-01
ZA200102003B (en) 2002-08-28
DK1112251T3 (da) 2003-09-01
JP2002525267A (ja) 2002-08-13
HUP0103341A2 (hu) 2002-02-28
CO5150230A1 (es) 2002-04-29
RU2230739C2 (ru) 2004-06-20
TW530046B (en) 2003-05-01
EP1112251A1 (de) 2001-07-04
JP4767413B2 (ja) 2011-09-07
PT1112251E (pt) 2003-09-30
CN1316991A (zh) 2001-10-10

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